Headache in Pregnancy · 2020-03-18 · Headache in Pregnancy E. Anne MacGregor, MB BS, MD, FFSRH, MICR ABSTRACT Purpose of Review: This article provides an overview of the diagnosis

Headache in PregnancyE. Anne MacGregor, MB BS, MD, FFSRH, MICR

ABSTRACTPurpose of Review: This article provides an overview of the diagnosis andmanagement of primary and secondary headaches that may occur during pregnancyand postpartum. Headache presenting in pregnancy is of significant concern to theaffected woman. Quick and correct diagnosis leads to the optimal management,minimizing risks to the pregnancy.Recent Findings: Several strategies have been developed to distinguish secondaryheadaches that need urgent assessment and management from benign primary andsecondary headaches and to minimize the risk of misdiagnosis. Recent guidelines forthe drug treatment of headaches are considered in the context of updatedinformation on the safety of drugs in pregnancy and lactation.Summary: Primary headaches are common and typically improve during pregnancy.Management during pregnancy and lactation is similar to management in thenonpregnant state, with a few exceptions. Secondary causes of headache that aremore likely to occur during pregnancy include cerebral venous thrombosis, posteriorreversible encephalopathy syndrome resulting from eclampsia, postYdural punctureheadache, stroke, and pituitary apoplexy.

Continuum (Minneap Minn) 2014;20(1):128–147.

INTRODUCTIONHeadaches are common during thereproductive years and are just aslikely to occur in pregnancy as innonpregnant women. Most headacheswill be benign with no impact on thepregnancy. However, the potentialeffects of drugs on the fetus and theincreased risk of certain secondaryheadaches during pregnancy call forcareful assessment and managementof the pregnant woman presentingwith headaches.

Approximately half of the pregnan-cies in the United States are unplanned;of these, over 40% continue to birth.Many women take medication duringpregnancy, with each woman taking anaverage of four to five different medica-tions.1 Drugs and other teratogensexert their greatest effects on the fetusduring the second and third months ofgestation, so health care providersneed to advise women on safe and

effective treatment of headaches dur-ing pregnancy and lactation.

CLASSIFICATION OF HEADACHESThe International Classification of Head-ache Disorders categorizes primary andsecondary headaches.2 Primary head-aches account for the majority of head-aches during pregnancy. Of the primaryheadaches, tension-type headache andmigraine generally improve duringpregnancy. The effect of pregnancyon cluster headache is limited becauseof the rarity of the condition, and thedata are conflicting. A common cause ofdaily headache in a patient with ahistory of primary headache is medica-tion overuse headache. Secondarycauses of headache that are more likelyto occur during pregnancy includecerebral venous thrombosis, posteriorreversible encephalopathy syndrome(PRES) resulting from eclampsia,postYdural puncture headache, stroke,

Address correspondence toProfessor E. Anne MacGregor,Barts Sexual Health Centre,St Bartholomew’s Hospital,London EC1A 7BE,United Kingdom,[email protected].

Relationship Disclosure:

Professor MacGregor hasacted as a paid consultant toand/or her department hasreceived research fundingfrom Addex Therapeutics;Allergan, Inc; AstraZeneca;Berlin-Chemie AG;BTG International Ltd;Endo Pharmaceuticals Inc;GlaxoSmithKline; theMenarini Group; Merck & Co,Inc; POZEN Inc; and UniPath.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Professor MacGregordiscusses the use of severaldrugs for the treatment ofheadaches, none of which arelabeled by the US Food andDrug Administration for use inpregnancy.

* 2014, American Academyof Neurology.

128 www.ContinuumJournal.com February 2014

Review Article

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and pituitary apoplexy (Table 7-1). Inaddition, headaches can be symptom-atic of emotional stress.3

ASSESSING THE PREGNANTWOMAN WITH HEADACHEThe history should focus on estab-lishing the likelihood that the headachehas some secondary cause or defining itamong the primary headache disorders.Specific questions can help to evaluate

secondary causes of headache that mayneed urgent assessment (Table 7-2).Because secondary headaches can oc-cur in a patient with a long-standinghistory of primary headache, it isimportant to elicit new symptoms. Thisapproach can separate those who needfurther investigation from those withbenign secondary headaches or typicalhistories of primary headaches. Thelatter can be reassured, treated, and

KEY POINTS

h Of the primaryheadaches, tension-typeheadache and migrainegenerally improveduring pregnancy.

h A common cause ofdaily headache in apatient with a historyof primary headache ismedication overuseheadache.

h Because secondaryheadaches can occurin a patient with along-standing history ofprimary headache, it isimportant to elicit newsymptoms.

TABLE 7-1 International Classification of Headache Disorders,3rd Edition (Beta Version)a

Primary Headaches

1. Migraine

2. Tension-type headache

3. Trigeminal autonomic cephalalgias

4. Other primary headache disorders

Secondary Headaches

5. Headache attributed to trauma or injury to the head and/or neck

6. Headache attributed to cranial or cervical vascular disorder

6.1 Headache attributed to ischemic stroke or TIA

6.2.1 Headache attributed to nontraumatic intracerebral hemorrhage

6.2.2 Headache attributed to nontraumatic subarachnoid hemorrhage

6.3 Headache attributed to unruptured vascular malformation

6.6 Headache attributed to cerebral venous thrombosis

6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome

6.9 Headache attributed to pituitary apoplexy

7. Headache attributed to nonvascular intracranial disorder

7.1.1 Headache attributed to idiopathic intracranial hypertension

7.2.1 PostYdural puncture headache

8. Headache attributed to a substance or its withdrawal

8.2 Medication-overuse headache

9. Headache attributed to infection

10. Headache attributed to disorder of homeostasis

10.3.4 Headache attributed to preeclampsia or eclampsia

11. Headache or facial pain attributed to disorder of the cranium, neck, eyes,ears, nose, sinuses, teeth, mouth, or other facial or cervical structures

12. Headache attributed to psychiatric disorder

Painful Cranial Neuropathies, Other Facial Pains, and Other Headaches

13. Painful cranial neuropathies and other facial pains

14. Other headache disorders

a Data from Headache Classification Committee of the International Headache Society, Cephalalgia.2

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followed by the neurologist or primarycare physician as appropriate.

Risk factors for pregnancy-relatedstroke include diabetes mellitus,migraine with aura, preexisting hyper-tension, hypertensive disorders ofpregnancy, sickle cell disease, struc-tural heart disease, and thrombophilia.Complications of pregnancy andthe puerperium associated with in-creased risk of stroke include anemia,hyperemesis gravidarum, thrombocyto-penia, postpartum hemorrhage, andinfection. Depressive disorders oftenpresent with frequent prepregnancyheadache, which is a strong predictorof poor general and emotional healthduring pregnancy.3,4

Examination should focus on assess-ment for signs of concerning diagnosessuch as infection or hemorrhage; severehypertension; and neurologic signs in-

cluding papilledema or hemorrhageson funduscopy, neck stiffness, alteredconsciousness, or weakness.

Symptoms and Signs ofSecondary Headachesin PregnancyAlthough stroke can occur duringpregnancy, it is more likely to occurin the 6 weeks postpartum. Focalneurologic symptoms and signs withor without alterations in consciousnessare typical of stroke. Headache accom-panies ischemic stroke in 17% to 34%of cases and is usually nonspecific inquality and of moderate intensity.

Subarachnoid hemorrhage typicallypresents as an abrupt-onset thunder-clap headache that is intense andincapacitating. It is often unilateral andaccompanied by nausea, vomiting, neckstiffness, and fluctuating consciousness.

TABLE 7-2 Warning Signs and Symptoms for Secondary Headaches

Signs and Symptoms Possible Diagnosis

Thunderclap headache (intense headachewith abrupt or ‘‘explosive’’ onset)

Subarachnoid hemorrhage

Postpartum angiopathy

Pituitary apoplexy

Headache with atypical aura (duration91 hour, or including motor weakness)

TIA

Ischemic stroke

Fever Meningitis

History of HIV or syphilis Meningoencephalitis

History of cancer Secondary brain metastases

Postural headache (avoids lying flator standing up)

Subarachnoid hemorrhage

Cerebral venous thrombosis

Intracranial hypotension

Progressive headache worsening overweeks or months; cognitive or personalitychanges symptoms of raised intracranialpressure (drowsiness, postural-relatedheadache, vomiting); new-onset seizures;progressive neurologic deficit (weakness,sensory loss, dysphasia, ataxia)

Visual disturbance/scotoma

Intracranial space-occupying lesion

Idiopathic intracranial hypertension

Cerebral venous thrombosis

Elampsia

Preeclampsia

Idiopathic intracranial hypertensionTIA = transient ischemic attack; HIV = human immunodeficiency virus.


Headache in Pregnancy


If neuroimaging is negative, lumbarpuncture is imperative. Sentinel head-ache associated with a leaking cerebralaneurysm can precede subarachnoidhemorrhage in up to 50% of cases,typically occurring a couple of weeksbefore the aneurysm ruptures. An acutethird nerve palsy, with retro-orbital painand a dilated pupil, indicates impendingrupture of a posterior communicatingcerebral artery aneurysm.

A nonspecific unremitting headacheis a common symptom of cerebralvenous thrombosis, as seen in Case 7-1.Cerebral venous thrombosis is esti-mated to occur in 1 per 2500 to 10,000pregnancies and is most likely inwomen with hypercoagulability. Head-ache may be the only finding, but often

it is associated with seizures, focalneurologic symptoms, and raised intra-cranial pressure.

The combination of hypertension andproteinuria in a pregnant woman suggestspreeclampsia and needs urgent manage-ment to reduce blood pressure andprevent eclampsia. Headache is a senti-nel symptom of eclamptic seizure inaround three-quarters of women withpreeclampsia. The headache is progres-sive and refractory to analgesia. Manypatients with preeclampsia present withheadache due to hypertensive enceph-alopathy (ie, PRES) without seizures.Blurred vision, scotoma, and flashinglights in such patients can be misdiag-nosed as migraine aura. Within thespectrum of preeclampsia/eclampsia,

Case 7-1A 26-year-old woman who was 25 weeks pregnant with her first childwas admitted after having a generalized tonic-clonic seizure. During the8 days before admission, she had a constant, nonthrobbing headacheassociated with nausea and vomiting. She had taken the combined oralcontraceptive pill from 18 to 25 years of age and had no problems otherthan headaches in the hormone-free interval, which resolved when shetook the pill continuously, without a break; she stopped taking the pillwhen she was 25 years old because she wished to become pregnant andconceived 6 months later. Apart from nausea and vomiting during earlypregnancy, she had been well.

On examination, blood pressure was normal, temperature was 36.9-C,and body mass index was 28.4 kg/m2. Remaining physical and neurologicassessments, including optic funduscopy, were normal.

Laboratory tests were all within normal ranges. A noncontrast brainMRI scan and MR venogram revealed a superior sagittal sinus thrombosis.She was treated with low-molecular-weight heparin for the remainder ofthe pregnancy and for 6 weeks postpartum. Her headache resolved within3 days of starting treatment, and the remainder of her pregnancy wasuneventful, with a spontaneous normal delivery of a healthy boy at 39weeks.

Comment. This pregnant migraineur presented with a new headache.While it is more common in the peripartum, cerebral venous thrombosisshould be excluded in patients with progressive headache with seizureduring pregnancy. Focal neurologic deficits and coma can also occur.Funduscopy may show signs of raised intracranial pressure, but brainimaging is indicated even if normal. This woman was fortunate to receivean early diagnosis and management, which led to a full recovery withoutcompromising the pregnancy. Delayed diagnosis can result in permanentdysfunction and death.



while some patients will present withPRES, others will present with the rever-sible cerebral vasoconstriction syn-drome (RCVS), called postpartumangiopathy when it occurs in the post-partum period. This is a cerebral vaso-constriction syndrome that can becomplicated by ischemic stroke. It usu-ally occurs in the week after an uncom-plicated pregnancy and delivery. It canmimic subarachnoid hemorrhage,presenting as a thunderclap headacheassociated with fluctuating neurologicdeficits and sometimes seizures. Angi-ography reveals a classic ‘‘string ofbeads’’ appearance with areas of steno-sis and dilation in multiple intracranialvessels. There is strong evidence for thebenefit of magnesium sulfate forpreeclampsia/eclampsia. The authorsof the article ‘‘Cerebrovascular Disor-ders Complicating Pregnancy’’ in thisissue of recommendthis therapy for preeclampsia/eclampsiain all of its forms, along with promptcontrol of blood pressure. For furtherdetails regarding PRES and RCVS, referto ‘‘Cerebrovascular Disorders Compli-cating Pregnancy’’ by Drs Steven K.Feske and Aneesh B. Singhal in thisissue of .

Pituitary apoplexy, resulting fromspontaneous hemorrhagic infarctionof the pituitary gland, is rare but lifethreatening. It presents with a retro-orbital, frontal, or diffuse thunderclapheadache associated with nausea andvomiting, fluctuating consciousness,hypotension, and visual loss. If MRI isnot available, an urgent pituitary CTscan is indicated.

Idiopathic intracranial hypertensionpresents with a diffuse, nonthrobbing,daily headache aggravated by cough-ing and straining. Signs includepapilledema, an enlarged blind spot,visual field defect, or sixth nerve palsy.Lumbar puncture (performed afterbrain imaging excludes an intracranial

mass lesion) reveals increased CSFpressure with normal CSF chemistry.Headache improves with reduction inCSF pressure.

PostYdural puncture headache af-fects one-third of patients after lumbarpuncture with onset typically within 5days of the procedure. The headacheis postural, worsening on standing andimproving when lying flat. Associatedsymptoms include neck stiffness, tin-nitus, hyperacusia, photophobia, andnausea. In the majority of cases, theheadache resolves within a week with-out further intervention. If conserva-tive methods fail, an epidural bloodpatch should be considered.

Symptoms and Signs of PrimaryHeadaches in PregnancyEach primary headache has a specificpattern of symptoms in the absence ofclinical signs (Figure 7-1). The historyis diagnostic, and investigations areonly required to rule out a suspectedsecondary headache.

Tension-type headache. Head-aches that lack associated symptoms,in an otherwise well person who is notoverusing medication, are likely to betension-type headaches.

In the majority of women, tension-type headache will improve duringpregnancy.

Migraine. Recurrent episodic head-aches that last between 4 and 72hours and are associated with photo-phobia, nausea, and disability in anotherwise well person are typical fea-tures of migraine.

Up to 60% to 70% of women withpreexisting migraine report fewer mi-graine attacks during pregnancy.Women with a history of menstrualor menstrually related migraine with-out aura are more likely to reportimprovement than for those with noevidence of a menstrual association.6

Migraine is likely to continue throughout

KEY POINTS

h Each primary headachehas a specific patternof symptoms in theabsence of clinical signs.

h Headaches that lackassociated symptoms,in an otherwise wellperson who is notoverusing medication,are likely to betension-type headaches.

h Recurrent episodicheadaches that lastbetween 4 and72 hours and areassociated withphotophobia, nausea,and disability in anotherwise well personare typical features ofmigraine.




pregnancy and postpartum if it doesnot improve by the end of thefirst trimester. Breast-feeding is en-couraged because it maintains theprotective effect of pregnancy onmigraine headache during the post-partum period.

Women who have preexisting mi-graine with aura do not experiencethe same benefit and are more likely

to continue to have attacks duringpregnancy. As seen in Case 7-2,women may develop aura for the firsttime during pregnancy, irrespective ofwhether they have a past history ofmigraine without aura.7

Women can be reassured thatthere is evidence that migraine doesnot adversely affect the outcome ofpregnancy in otherwise healthy women.8

FIGURE 7-1 Algorithm for the diagnosis of primary headaches.

Adapted with permission from MacGregor A, Wiley Blackwell.39

B 2008, John Wiley and Sons.



However, migraine during pregnancyis associated with increased riskof arterial and venous thrombosis,preeclampsia, and gestational hy-pertension.9Y17 Pregnant womenwith migraine should be moni-tored for these conditionsVfor ex-ample, rising systolic or diastolic bloodpressure should prompt a check forproteinuria.

Disorders such as thrombocytope-nia, cerebral venous sinus thrombosis,or imminent eclampsia may mimicaura and should be excluded in wom-en presenting with their first attack ofaura during pregnancy.

Cluster headache. Cluster head-ache affects fewer than 1 in 500people, and in contrast to migraineand tension-type headache, it is muchmore common in men than in women.It is frequently misdiagnosed as mi-

graine despite stereotypical symptomsof strictly unilateral headache andautonomic symptoms lasting up to 2hours in clusters typically lasting 6 to8 weeks. Data on cluster headacheduring pregnancy are limited, but ithas been noted that women whohave their first cluster headache beforetheir first pregnancy have fewer chil-dren than those who already havechildren at the time of their firstattack.18,19 While the possibilityof hypofertility has been raised, themore likely explanation is that womenchoose not to conceive as theyare concerned about the effects ofmedication for cluster headache onthe outcome of pregnancy.19

Medication overuse headache.Medication overuse headache affectspeople with a history of a primaryheadache that has becomemore frequent

KEY POINT

h Cluster headache isfrequentlymisdiagnosed asmigraine despitestereotypical symptomsof strictly unilateralheadache andautonomic symptomslasting up to 2 hours inclusters typically lasting6 to 8 weeks.

Case 7-2A 34-year-old woman was 32 weeks pregnant with her first child. Whileat work she developed blurred vision to the right, difficulty with speech,and tingling, numbness, and weakness of her right arm lasting 20 minutes.This was followed by nausea and a left temporal headache lasting 5 hours.By the time she was seen in the emergency department, all symptoms hadresolved apart from the headache. She had a history of migraine withoutaura since the age of 15 years but no other history of note. She took noregular medication other than pregnancy supplements. On examination,her blood pressure was 110/70 mm Hg, temperature was 36.8-C, andbody mass index was 23.6 kg/m2. Remaining physical and neurologicassessments, including optic funduscopy, were normal.

Laboratory tests, thrombophilia screen, EEG, echocardiogram, andnoncontrast brain MRI were normal. By the time the investigations werecomplete, the headache had resolved, and the patient felt ‘‘back tonormal.’’ Migraine with aura was considered the most likely diagnosis. Shewas discharged with advice to return if her condition deteriorated at alland with an analgesic/antiemetic combination to take at the onset ofsymptoms if they recurred. She had three further attacks during theremainder of the otherwise uneventful pregnancy, all of which respondedto medication.

Comment. Although migraine without aura typically improves duringpregnancy, migraine with aura can occur for the first time in women withor without previous attacks of migraine without aura. While migraineitself, with or without aura, poses no risk to the pregnancy, migraine inpregnancy is a risk factor for hypertensive disorders of pregnancy, so thesewomen should be monitored carefully.




(Case 7-3). Medication overuse head-ache should always be excluded inanyone using symptomatic treatmentsfor headache more often than 2 to 3days a week or taking frequent caf-feine in any form. It is an avoidablecause of treatment failure, as head-ache becomes resistant to all lines ofmanagement until symptomatic drugsare withdrawn. Drug withdrawal typi-cally resolves headache frequency,and residual episodic headache canbe treated appropriately.

INVESTIGATIONS DURINGPREGNANCY AND LACTATIONInvestigations are indicated only toexclude suspected secondary head-ache resulting from underlying pathol-ogy. For a discussion of brain imaging

during pregnancy, see the article ‘‘Neu-roradiology in Women of ChildbearingAge’’ by Drs Riley Bove and JoshuaKlein in this issue of .

MANAGEMENT OF PRIMARYHEADACHES IN PREGNANCYNonpharmacologicNonpharmacologic treatment shouldbe considered as the initial step in themanagement of tension-type head-ache or migraine but is ineffective forcluster headache, which can only becontrolled with medication.

The most frequently reported trig-gers for tension-type headache andmigraine are stress (mental or physi-cal), irregular or inappropriate meals,high intake or withdrawal of coffee

Case 7-3A 27-year-old woman presented at 17 weeks of pregnancy with dailyheadaches. She had had migraine without aura since she was 11 years old.One year earlier, she had developed daily headaches and was diagnosedwith medication overuse headache as a consequence of frequent use oftriptans. She stopped this medication at that time and was started ontopiramate. She had a very severe headache for a week, after whichsymptoms resolved. The pattern of headache settled to one migraineattack every 4 to 6 weeks, which responded to a triptan, and she was freeof symptoms between attacks.

At the current presentation, her diaries showed a fluctuating pattern ofheadache over the preceding months, with a gradual increase in headachefrequency beginning when she stopped topiramate 3 months earlier tobecome pregnant. After she realized she was pregnant, she used onlyacetaminophen with codeine, which she had been taking most days, as shewas worried that she would develop a severe migraine and be unable toget to work. Vital signs were within normal range, and physical andneurologic examination was unremarkable.

Medication overuse headache was diagnosed, and she chose to stopanalgesics without additional support. She was advised that a severemigraine could be treated with IV magnesium sulfate, if necessary. Atfollow-up 2 weeks later, she reported that she had been unwell for thefirst week since stopping analgesics but felt much better in the last weekand had not had any further headaches.

Comment. Medication overuse headache is a common cause of dailyheadaches in patients with a history of primary headaches. The key findingis the use of symptomatic drugs for headache on more days than not in theabsence of any red flags in the history and in the presence of a normalexamination.



and other caffeine-containing drinks,dehydration, sleep disorders, toomuch or too little sleep, and reducedor excessive physical exercise.20,21

Pregnant women with tension-typeheadache or migraine should be en-couraged to avoid skipping meals, totake regular exercise, to drink plentyof fluids, and to maintain a regularsleep pattern. Alcohol and smokingare potentially harmful to the fetus andshould be avoided during pregnancy.

Nondrug therapies such as relaxa-tion, biofeedback, and physical thera-py are safe and may be effective inpregnancy.22,23 Acupuncture may alsotreat nausea and vomiting in preg-nancy in addition to headache.24Y26

Coenzyme Q10 daily is effective formigraine prophylaxis and, when takenduring pregnancy, has been associatedwith a significant reduced risk of pre-eclampsia.27,28 Similarly, magnesiumsupplements, which can be used formigraine prophylaxis, can halve therisk of eclampsia, with no evidence ofadverse effects on pregnancy.29,30 Seethe section on complementary medi-cines during pregnancy and lactationfor further details about coenzymeQ10 and magnesium during pregnancyand lactation.

Drug Treatment of Headache inPregnancy and LactationDrug use during pregnancy is com-mon, and many women continue touse their usual headache medication,including triptans, throughout preg-nancy.31 The most comprehensiveguidelines for the drug treatment ofprimary headaches are those devel-oped by the European Federation ofNeurological Societies.5,29,32 Mostdrugs are not licensed for use inpregnancy so should only be consid-ered if the potential benefits to thewoman and fetus outweigh the poten-tial risks. As discussed in Case 7-4,

women are often very concernedabout the effects that medicationmay have on the pregnancy. Thewoman should be given sufficientinformation about any known risks tomake her own decision about druguse, with clear documentation of thediscussion.

The US Food and Drug Adminis-tration (FDA) pregnancy labeling hasfive categories: A, B, C, D, and X(Appendix A). These categories canbe misleading because categories C,D, and X are not only based on riskbut consider risk versus benefit, sodrugs in each of these three catego-ries may pose similar risks. Severaladditional sources in the United Statesprovide information on the safety ofdrugs during pregnancy and lactation,and these have been reviewed toproduce the evidence for the recom-mendations below.

Symptomatic treatment. Thesymptomatic treatment of headachesduring pregnancy and lactation isthe same as for the nonpregnant state,with some exceptions (Table 7-3and Table 7-4).

Analgesics. Data from large-cohortand case-control studies confirm thesafety of therapeutic doses (4 g or lessper day) of acetaminophen duringpregnancy and lactation. It is theanalgesic of choice for the short-termrelief of mild to moderate pain andpyrexia.

While aspirin can be taken duringthe first and second trimesters ofpregnancy, it is best avoided near termbecause of increased risk of prolongedlabor, postpartum hemorrhage, andneonatal bleeding. Aspirin, in commonwith nonsteroidal anti-inflammatorydrugs (NSAIDs), has been associatedwithpremature closure of the fetal ductusarteriosus. Aspirin is excreted in breastmilk, and although occasional use by themother is unlikely to cause adverse effect,

KEY POINTS

h Pregnant women withtension-type headacheor migraine should beencouraged to avoidskipping meals, to takeregular exercise, to drinkplenty of fluids, and tomaintain a regular sleeppattern.

h Nondrug therapiessuch as relaxation,biofeedback, andphysical therapy aresafe and may beeffective in pregnancy.




it should not be taken regularly duringbreast-feeding because of the theoreticalrisk of Reye syndrome and impairedplatelet function in susceptible infants.

Nonsteroidal anti-inflammatorydrugs. Ibuprofen is the NSAID ofchoice during the first or secondtrimester. NSAIDs should be avoidedduring the third trimester becausechronic use or high doses after 30weeks are associated with an increased

risk of premature closure of the ductusarteriosus and oligohydramnios. Theconcentration of NSAIDs in breastmilk is very low so treatment duringbreast-feeding is unlikely to affect theinfant.

Opiates. Although safe for treatmentof moderate to severe pain in preg-nancy, opiates are inappropriate formigraine because they aggravate nauseaand reduce gastric motility. Chronic use

Case 7-4A 35-year-old woman presented when she was 13 weeks pregnant withher second child. She had migraine without aura as a teenager but wasfree of attacks during her twenties. Her first pregnancy, 7 years earlier,had been uneventful; 8 months before this presentation, she had amiscarriage at 9 weeks. Since the birth of her first child, she had onlyoccasional attacks, but over the previous year, she had migraine twice amonth that did not always respond to sumatriptan. She had startedamitriptyline 50 mg/d, which reduced the frequency to one attack every 4to 6 weeks, which she could then control with sumatriptan. She continuedon this combination during the second pregnancy and was concerned thatthis was the reason for her miscarriage. She stopped sumatriptan andamitriptyline as soon as she realized that she was pregnant again. Duringthe past 12 weeks, she had had three migraine attacks, treated withacetaminophen and codeine. This treatment was not effective, and shehad missed several days from work. She was concerned that anymedication may increase her chances of another miscarriage but wasequally worried that she would not be able to continue work. Other thanmild pregnancy-related nausea in the mornings, she was fit and well andtook only pregnancy supplements. It was explained to her that migrainedid not have any adverse effect on the outcome of pregnancy and neitherdid most migraine medications, including amitriptyline. The importanceof regular snacks and hydration to help migraine and the morningnausea was discussed. A combination of a nonsteroidal anti-inflammatorydrug and an antiemetic was considered for symptomatic treatment,understanding that she could use this until the 30th week of pregnancy,with the option of taking sumatriptan if necessary. Given that migrainewithout aura often improves after the first trimester of pregnancy,preventive treatment was deferred. At her review appointment 6 weekslater, she reported only one further attack at 11 weeks of pregnancyand none since.

Comment. Women are often concerned that they are responsible for amiscarriage, so it is important to remind them that at least 10% ofpregnancies result in miscarriage, most occurring during the first trimesteras a result of a genetic abnormality. Balancing risk and benefit ofmedication for migraine is an important consideration particularly sincemigraine itself has no adverse effect on the pregnancy. However, anuntreated migraine can result in significant morbidity.



TABLE 7-3 Drugs Used for Acute Treatment of Headache During Pregnancy

DrugFDA PregnancyCategorya Notes

AnalgesicsAcetaminophen B First-line; amounts in breast milk are much

less than doses usually given to infants

Aspirin C Second line; use in first and second trimestersonly; category D in third trimester

Diclofenac B Second line; use in first and second trimestersonly; category D in third trimester

Ibuprofen B Second line; nonsteroidal anti-inflammatorydrug of choice; use in first and second trimestersonly; category D in third trimester

Indomethacin C Use in first and second trimesters only; avoidfrom 30 weeks; category D in third trimester

Mefenamic acid C Use in first and second trimesters; avoid from30 weeks; category D in third trimester

Naproxen B Use in first and second trimesters only; avoidfrom 30 weeks; category D in third trimester

AntiemeticsMetoclopramide B

Prochlorperazine C

Promethazine C

BarbituratesButalbital C Category D if used in high doses at term or

for prolonged periods

ErgotsDihydroergotamine X

Ergotamine X

Opiates Opiates not recommended for migraineCodeine C

Meperidine B Category D if used in high doses at term orfor prolonged periods

Morphine C

Tramadol C

TriptansAlmotriptan C

Eletriptan C

Frovatriptan C

Naratriptan C

Rizatriptan C

Sumatriptan C Third line; consider for severe unresponsiveattacks

Zolmitriptan C

Other drugsPrednisone or prednisolone C

FDA = US Food and Drug Administration.a Please see Appendix A for the US Food and Drug Administration Pregnancy Category descriptions.




of opiates in later pregnancy has beenassociated with neonatal withdrawalsymptoms. Adverse effects during lac-tation are unlikely. However, some

women metabolize opiates slowly,which can cause higher levels of opiatesto pass into their breast milk, resultingin infantile drowsiness and sedation.

TABLE 7-4 Drugs for Acute Treatment of Headache During Lactation

Drug Level of Risk Notes

AnalgesicsAcetaminophen Minimal risk First line; amounts in breast milk are much

less than doses usually given to infantsAspirin Caution

Diclofenac Minimal risk Second line; short half-life

Ibuprofen Minimal risk Second line; nonsteroidal anti-inflammatorydrug of choice; short half-life; amounts inbreast milk are much less than doses usuallygiven to infants

Indomethacin Benefit likely to outweigh risk Used therapeutically in infants but drugs withmore data of use in lactation preferred

Mefenamic acid Caution Drugs with more data of use in lactation preferred

Naproxen Benefit likely to outweigh risk Drugs with short half-life preferred

Antiemetics

Cyclizine Minimal risk First line

Metoclopramide Minimal risk

Prochlorperazine Minimal risk

Promethazine Minimal risk First line

BarbituratesButalbital Caution

ErgotsDihydroergotamine Contraindicated

Ergotamine Contraindicated

Opiates Opiates not recommended for migraine

Codeine Benefit likely to outweigh risk May cause infant sedation; non-narcoticanalgesic preferred

Morphine Benefit likely to outweigh risk May cause infant sedation; non-narcoticanalgesic preferred

Morphine Benefit likely to outweigh risk May cause infant sedation; non-narcoticanalgesic preferred

Tramadol Benefit likely to outweigh risk

TriptansAlmotriptan Insufficient data

Eletriptan Benefit likely to outweigh risk

Frovatriptan Insufficient data Long half-life; drugs with short half-life preferred

Naratriptan Insufficient data

Rizatriptan Insufficient data

Sumatriptan Minimal risk Third line; consider for severe unresponsive attacks

Zolmitriptan Insufficient data



Barbiturates. Only limited humandata are available for butalbital duringpregnancy. Phenobarbital has beenassociated with teratogenicity andcan cause neonatal withdrawal andhemorrhagic disease of the newborn.It is excreted into breast milk andaccumulates in infants’ blood, causingsedation and withdrawal symptoms.

Antiemetics. Metoclopramide, pro-chlorperazine, and promethazine havebeen used widely in pregnancy andlactationwithout reports of adverse effects.

Triptans. Women who have takentriptans during pregnancy can bereassured that there is evidence tosupport no adverse outcome. How-ever, this is not the same as evidence toconfirm safety, so continued use dur-ing pregnancy is not recommendedunless no other treatment is effective.

Data from the Sumatriptan/Naratriptan/Treximet Pregnancy Regis-try (from 1996 to 2011) are reassuringand confirm that inadvertent exposureto sumatriptan during pregnancy hasnot been associated with adverse out-comes. Therefore, if clinically appro-priate, sumatriptan may be consideredfor the acute treatment of migraineduring pregnancy if no other treat-ments are effective. However, a smallincreased risk of specific birth defectscannot be excluded. The low level ofexcretion of sumatriptan in breastmilk suggests that continued breast-feeding following its use does notpose a significant risk to the infant.Data on other triptans are insufficient.

Ergots. Ergotamine and dihydroer-gotamine are contraindicated, becauseuterine hypertonicity and vascular dis-ruption increase the risk of miscar-riage. They should not be used duringbreast-feeding because of reportednausea, vomiting, diarrhea, and weak-ness in the breast-feeding infant andsuppression of prolactin secretion andlactation in the mother.

Drugs used for prophylaxis. Re-striction on drugs used for prophylaxisfor headache during pregnancy andlactation is greater than on drugs usedfor symptomatic treatment, but anumber of options are availablethat pose minimal risks to the unbornor breast-feeding child (Table 7-5and Table 7-6).

Low-dose aspirin. Low-dose aspirin(no more than 150 mg/d) has beenextensively studied in preeclampsiaduring pregnancy, with no increasein bleeding complications and negligi-ble effects on the ductus arteriosus.

Beta-blockers. If prophylaxis is con-sidered necessary during pregnancy,the lowest effective doses of propra-nolol or metoprolol are the drugs ofchoice. If beta-blockers are used in thethird trimester, treatment should bestopped 2 to 3 days before delivery inorder to reduce the likelihood of fetalbradycardia and a reduction in uterinecontraction. Infants exposed to pro-pranolol in utero should be monitoredfor neonatal bradycardia, hypotension,and hypoglycemia. Propranolol or met-oprolol are the beta-blockers of choiceduring lactation.

Antidepressants. Low-dose amitrip-tyline 10 mg/d to 25 mg/d is an option.While data are conflicting regardinglimb deformities associated with useof high doses of amitriptyline duringpregnancy, no association has beenreported with low doses between 10and 50 mg/d used for pain manage-ment. Where possible, it is recom-mended that the dose be tapered 3 to4 weeks before delivery. Otherwise, thephysician should monitor the baby foradverse effects such as drowsiness,jitteriness, hyperexcitability, and suck-ling problems. Amitriptyline or nortrip-tyline are barely detectable in breastmilk and treatment of the mother withthese drugs is unlikely to affect theinfant adversely.




Data are conflicting on the risk ofcongenital malformations following usein early pregnancy of selective serotoninreuptake inhibitor (SSRI) or serotonin-

norepinephrine reuptake inhibitor(SNRI). Although several studies havedemonstrated no statistically significantincrease in risk, an increased risk of

TABLE 7-5 Drugs Used for Prophylaxis of Headache During Pregnancy

DrugFDA PregnancyCategorya Notes

Angiotensin-convertingenzyme inhibitorsLisinopril D Category C in first trimester

Angiotensin receptor blockersCandesartan D Category C in first trimester

AntiepilepticsGabapentin C

Topiramate D

Valproic acid X Teratogenic

Antiplatelet drugsAspirin C Doses e150 mg/d

Beta-blockersAtenolol D Propranolol or metoprolol

preferredMetoprolol C

Nadolol C Propranolol or metoprololpreferred

Propranolol C Beta-blocker of choice

Timolol C Propranolol or metoprololpreferred

Calcium channel blockersNifedipine C

Verapamil C No data on high doses inpregnancy

SSRIs/SNRIs Amitriptyline ornortriptyline preferred

Citalopram C

Escitalopram C

Fluoxetine C

Sertraline C

Venlafaxine C

TricyclicsAmitriptyline C

Nortriptyline COther drugsBotulinum toxin C

Lithium D Teratogenic

FDA = US Food and Drug Administration; SSRIs = selective serotonin reuptake inhibitors; SNRIs =serotonin-norepinephrine reuptake inhibitors.a Please see Appendix A for the US Food and Drug Administration Pregnancy Category descriptions.



TABLE 7-6 Drugs Used for Prophylaxis of Headache During Lactation

Drug Level of Risk Notes

Angiotensin II antagonistsCandesartan Insufficient data

Angiotensin-convertingenzyme inhibitorsLisinopril Insufficient data

AntiepilepticsGabapentin Benefit likely to

outweigh riskDoses up to 2.1 g/d produce relatively low levelsin infant serum; monitor infant for side effects

Topiramate Benefit likely tooutweigh risk

Doses up to 200 mg/d produce relatively low levelsin infant serum; monitor infant for side effects

Valproic acid Benefit likely tooutweigh risk

Low levels in infant serum; theoretical risk ofinfant hepatotoxicity; monitor for jaundice

Antiplatelet drugsAspirin Minimal risk Doses e150 mg/d

Beta-blockers Propranolol or metoprolol preferredAtenolol Concern

Metoprolol Benefit likely tooutweigh risk

Nadolol Concern

Propranolol Minimal risk Beta-blocker of choice; low levels in breast milk;no adverse reactions attributed

Timolol Concern Variable excretion into breast milk; limited data

Calcium channel blockersNifedipine Minimal risk

Verapamil Minimal risk Doses up to 360 mg/d produce low serum levelsin infant but no adverse reactions attributed

SSRIs/SNRIs Amitriptyline or nortriptyline preferred

Citalopram Concern Infant exposure lower with escitalopram

Escitalopram Benefit likely tooutweigh risk

Fluoxetine Concern Higher levels in breast milk than other SSRIs andlong-acting metabolite; other SSRIs preferredunless patient established on treatment

Paroxetine Benefit likely tooutweigh risk

Low levels in breast milk

Sertraline Benefit likely tooutweigh risk

Low levels in breast milk; no adverse reactionsattributed

Venlafaxine Benefit likely tooutweigh risk

Excreted into breast milk

TricyclicsAmitriptyline Minimal risk Low levels in breast milk

Nortriptyline Minimal risk Low or undetectable levels in breast milk

Other drugsBotulinum toxin Insufficient data

Lithium Contraindicated Teratogenic

SSRIs = selective serotonin reuptake inhibitor; SNRIs = serotonin-norepinephrine reuptake inhibitor.




cardiovascular malformations wassuggested in one large study. However,the absolute risk appears to be small.Use of any SSRI in late pregnancy mayresult in a mild, transient neonatalwithdrawal syndrome, which includescontinuous crying, irritability, jitteriness,or restlessness; shivering; fever; tremors;hypertonia or rigidity; tachypnea orrespiratory distress; feeding difficulty;sleep disturbance; hypoglycemia; andseizures. Exposure to SSRIs beyond 20weeks of gestation has been associatedwith persistent pulmonary hypertensionof the newborn, although the estimatedabsolute risk is less than 0.5%.

Antiepileptics. Risk of oral clefts isincreased after exposure to topiramatein pregnancy. Sodium valproate isassociated with a high risk of fetalabnormalities and is contraindicatedduring pregnancy in the absence ofepilepsy; it can be used during lacta-tion. Currently available data do notsuggest that gabapentin has any ad-verse effect on pregnancy, but it isconsidered at best to be a third-linemigraine prophylactic agent. Refer tothe article ‘‘Pregnancy and Epilepsy’’by Dr Cynthia Harden in this issue of

for a detailed discussionof antiepileptic agents and pregnancy.

Calcium channel blockers. Datafor verapamil are limited. It has atocolytic effect on the uterus, soshould be avoided in late pregnancy.No association with congenital anom-alies has been reported. Verapamil isexcreted in human milk with potentialfor adverse reactions in infants, whichis of particular concern with highdoses necessary for cluster headache,although no data are available.

Angiotensin receptor blockers.Case reports have described congenitalmalformations, fetal renal damage,oligohydramnios, skull ossification de-fects, and death in infants exposed toangiotensin receptor blockers in utero.

Angiotensin-converting enzymeinhibitors. Lisinopril is used for mi-graine prophylaxis. In common withother angiotensin-converting enzyme(ACE) inhibitors, it poses no signifi-cant fetal risk during the first trimes-ter. During the second and thirdtrimesters, it is toxic and teratogenic,causing prematurity, intrauterinegrowth retardation, renal tubular dys-plasia, severe oligohydramnios leadingto fetal distress, lung hypoplasia, skullhypoplasia, limb contractures, neona-tal hypotension, and anuria.

Botulinum toxin. No human datahave been published regarding terato-genicity of botulinum toxin, licensedfor chronic migraine, in pregnancyand lactation.

Lithium. Exposure to therapeuticdoses of lithium in pregnancy areassociated with teratogenic and othertoxic effects in the fetus and neonate.Opinions are conflicting as to whetherlithium should be stopped during thefirst trimester of pregnancy andrestarted in the second trimester. Iftreatment with lithium is indicated,combined specialist supervision by aneurologist and obstetrician is essen-tial. Lithium is excreted in breast milkand has been associated with adverseeffects in the infant.

Approach to Drug Treatment ofTension-Type Headache DuringPregnancy and LactationSymptomatic treatment with nonopioidanalgesics is appropriate for episodicattacks occurring on fewer than 2 daysper week.5 Prophylactic medicationsare seldom necessary and are onlyindicated for chronic tension-typeheadache or when headaches regularlyoccur more than 2 to 3 days aweek. Amitriptyline is the drug offirst choice for prophylaxis of tension-type headache during pregnancyand lactation.



Michael_Rogawski

Highlight

Approach to Drug Treatmentof Migraine During Pregnancyand LactationSymptomatic treatment of attacks in-cludes nonopioid analgesics andprokinetic antiemetics, which shouldbe limited to a maximum of 2 to 3treatment days per week (12 days permonth). Sumatriptan may be indicatedfor severe attacks during pregnancythat do not respond to first-line drugsand can be used during lactationwithout disruption to breast-feeding.Prophylaxis should be consideredwhen attacks are frequent or fail torespond to symptomatic management.

Analgesics can be used for symp-tomatic treatment. Most antiemeticscan be continued throughout preg-nancy and lactation. If prophylaxis isindicated during pregnancy or lactation,the lowest effective dose of propranololis the first-line recommendation. Ami-triptyline is also an option.

Approach to Drug Treatmentof Cluster Headache DuringPregnancy and LactationProphylaxis is the mainstay of manage-ment of cluster headache. Preferredtreatments during pregnancy and lac-tation are verapamil or prednisone/prednisolone.33 Cardiac conductionproblems affect about 20% of patientswith cluster headache taking verapa-

mil and are dependent on neitherduration nor dose. ECGs to assess PRinterval prolongation should be un-dertaken at baseline, before each doseincrement, and every 6 months duringlong-term treatment. Gabapentin is asecond-line prophylactic option dur-ing pregnancy and lactation. Lithium isan additional option for prophylaxisduring lactation but should not beused during pregnancy.

Acute treatment includes oxygen(100% at 7 L/min for 10 to 15 minutesat onset of attack) or subcutaneous orintranasal sumatriptan.33 No safetyconcerns exist regarding use of oxy-gen during pregnancy.34

Complementary MedicinesDuring Pregnancy and LactationMany pregnant women use dietary sup-plements during pregnancy, incorrectlyassuming that because they are not‘‘drugs’’ they must be safe (Table 7-7).Although some evidence suggests thatsupplementing deficient vitamins andminerals can be beneficial, megadoseregimens should be avoided.

The daily recommended dietaryallowances of riboflavin (Vitamin B2)for pregnant women is 1.4 mg, and 1.6mg for breast-feeding women.

Pregnant women are at risk ofvitamin D deficiency due to increasedfetal and neonatal demands during

TABLE 7-7 Complementary Supplements and Pregnancy and Lactationa

Supplements Notes

Coenzyme Q10 Insufficient data regarding safety for migraine prophylaxisduring pregnancy; compatible with breast-feeding

Magnesium sulfate Maximum of 350 mg/d

Vitamin B2 Recommended daily allowance doses only

Vitamin D 10 2g/d recommended for all pregnant andbreast-feeding women

a Use of megadose vitamin regimens should be avoided.




intrauterine growth and development.Vitamin D deficiency has also beenassociated with increased risk ofmigraine. Vitamin D supplements of10 2g/d (or equivalent) are currentlyrecommended for all pregnant andbreast-feeding women. Very highdoses of vitamin D can increase theserum calcium concentration, whichcould result in maternal, fetal, orneonatal hypercalcemia.

Scientific evidence is insufficient tosupport the safe use of coenzyme Q10during early pregnancy or breast-feeding. Supplementation with 100 mgcoenzyme Q10 twice daily from week20 of pregnancy has been shown toreduce the risk of preeclampsia inwomen at risk for the condition.

Magnesium sulfate is considered to becompatible with pregnancy and breast-feeding, but the FDA recommends anupper limit of 350 mg magnesiumsulfate daily.

EMERGENCY TREATMENTOF HEADACHEDuring pregnancy and lactation,prochlorperazine 10 mg or chlorprom-azine 25 mg to 50 mg by IM injectionare effective for emergency headacherelief even without additional analge-sia and, together with IV fluids, areusually sufficient to abort an attack. IVmagnesium sulfate 1 g given intrave-nously over 15 minutes was welltolerated and effective in a random-ized, single-blind, placebo-controlledtrial of 30 patients with migraine.35 Acombination of IV prochlorperazine10 mg every 8 hours and IV magne-sium sulfate 1 g every 12 hours wasused successfully to abort two casesof prolonged migraine aura duringpregnancy.36 Continuous administrationof magnesium sulfate injection beyond5 to 7 days in pregnancy should beavoided because it can cause low calciumlevels and bone changes in the baby.

Corticosteroids successfully treatintractable nausea and vomiting inhyperemesis gravidarum. A 6-day reduc-ing course of prednisolone (60 mg/d for2 days, 40 mg/d for 2 days, and 20 mg/dfor 2 days) can be considered totreat long-duration headache attacks,particularly if evidence of medicationoveruse is present.37 Chronic exposureto high doses of steroids in pregnancyshould be avoided as it may causefetal/neonatal adrenal suppression, andincreased incidence of congenitalanomalies, neonatal cataracts, and still-birth have been reported when thedrug is used throughout pregnancy.Prednisone/prednisolone is compatiblewith breast-feeding.

CONCLUSIONSThe majority of headaches occurringduring pregnancy and lactation arebenign and likely to improve withminimal intervention. However, preg-nancy can be a risk factor for certainpotentially life-threatening headachesthat require urgent evaluation. Theassessment of the pregnant patientwith headache relies on a directedhistory to elicit warning symptoms thatrequire immediate investigation andmanagement. Investigation of head-ache is the same as for nonpregnantwomen, although the threshold toconsider certain disorders must belower, and routine investigationsshould be deferred until postpartum.

It is important to minimize drugexposure in women who are planningpregnancy or who are at high riskof unplanned pregnancy. Many drugsand other teratogens exert their greatesteffects on the fetus during the secondand third months of gestation. If a drugis taken at any stage of pregnancy, it isessential that the woman be providedwith sufficient information about anyknown risks in order for her to makeher own decision about its use.

KEY POINT

h During pregnancy andlactation, prochlorperazine10 mg or chlorpromazine25 mg to 50 mg by IMinjection are effectivefor emergencyheadache reliefeven withoutadditional analgesia.



Nonpharmacologic managementand lifestyle changes can be effec-tive without the need for additionaldrug intervention and have the ad-vantage of continued benefit beyondpregnancy.

USEFUL WEBSITESSumatriptan/Naratriptan/TreximetPregnancy Registry, Kendle Internationalpregnancyregistry.gsk.com/sumatriptan.html

Rizatriptan Pregnancy Registry, Merck& Co, Incwww.merckpregnancyregistries.com/maxalt.html

Summary of Proposed Rule onPregnancy and Lactation Labellingwww.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093310.htm

National Library of Medicine Drugsand Lactation Database (LactMed)toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT

Organization of Teratology InformationSpecialists (OTIS)www.OTISpregnancy.org

Teratogen Information Service (TERIS)depts.washington.edu/terisweb/teris/

The International Classification of Head-acheDisorders, 3rd edition (beta version)www.ihs-classification.org/_downloads/mixed/International-Headache-Classification-III-ICHD-III-2013-Beta.pdf

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http://www.toxbase.org/upload/Pregnancy%20pdfs/Carbon%20Monoxide%202012.pdf



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