Headache during pregnancy and postpartum

INTRODUCTION — Headache is common among females in their childbearing years: In the Norwegian Head-HUNT study, 60 percent of females ≤40 years of age reported experiencing a headache within the previous year [1]. For patients with a history of headache, the effect of pregnancy on the frequency and severity of headache, the effect of headache on pregnancy outcome, and the fetal safety of maternal headache treatment are major concerns. For patients with new onset of headache during pregnancy or postpartum, a diagnostic evaluation is indicated and should include evaluation for pregnancy-related causes of headache. Preeclampsia with severe features always needs to be excluded in pregnant patients over 20 weeks of gestation with a headache.

This topic will discuss issues specific to diagnosis and management of headache in pregnant and postpartum patients. The diagnosis and treatment of headaches in the general population are reviewed separately. (See "Evaluation of headache in adults" and "Evaluation of the adult with nontraumatic headache in the emergency department".)

DIAGNOSTIC EVALUATION

Patients requiring prompt evaluation

Patients ≥20 weeks of gestation (evaluate for preeclampsia) — Preeclampsia must be considered in every pregnant patient over 20 weeks of gestation with headache.

●Prevalence – Among pregnant patients with no history of a headache and the onset of new or atypical headache who present for evaluation, one-third have preeclampsia [2].

●Diagnostic criteria – Criteria for diagnosis of preeclampsia are described in the table and form the basis for evaluation (table 1). The diagnosis can be excluded in most normotensive patients. (See "Preeclampsia: Clinical features and diagnosis".)

●Clinical findings – Headache is a feature of the severe spectrum of preeclamptic disease and a potential precursor of eclampsia (preeclampsia with seizure) [3]. The headache is typically diffuse (holocephalic), constant, throbbing, and mild to severe in intensity. Blurred vision, photophobia, and confusion and alteration in the level of consciousness may occur. These symptoms are similar to those of migraine, except migraine pain is frequently unilateral. In patients with mildly increased blood pressure that may be due to pain, the diagnosis of preeclampsia-related headache is supported by the presence of other severe features of the disease: scotomata or other visual problems (eg, blurred vision, double vision, photophobia, amaurosis, hemianopsia), epigastric pain, or laboratory findings of thrombocytopenia, elevated liver chemistries, hemolysis, and/or elevated creatinine.

The neurologic examination is usually normal in preeclampsia. Focal neurologic symptoms suggest complicated preeclampsia (eg, stroke) or an alternative diagnosis (eg, migraine with aura, stroke unrelated to preeclampsia). Although seizure is the key finding of eclampsia, it also occurs with other intracranial pathology, including cerebral venous thrombosis, hemorrhage, and tumor. (See "Eclampsia".)

●Pathophysiology – The cause of headache in preeclampsia/eclampsia is not known, but may be related to increased cerebral perfusion pressure (eg, hypertensive encephalopathy) [4,5], cerebral ischemia from vasoconstriction (reversible cerebral vasoconstriction syndrome [RCVS]) [4], posterior reversible encephalopathy syndrome (PRES) [6], cerebral edema, or microhemorrhages [7]. (See "Reversible posterior leukoencephalopathy syndrome" and "Cerebrovascular disorders complicating pregnancy".)

●Consultation – Patients in whom preeclampsia/eclampsia is suspected should have an obstetric or maternal-fetal medicine consultation. A neurologist or neurosurgeon should be consulted in those with an abnormal neurologic examination or severe headache that persists after preeclampsia/eclampsia has been excluded.

Patients with symptoms potentially associated with a serious underlying disorder — Pregnant patients with the following signs/symptoms associated with headache are more likely to have a serious underlying disorder that may or may not be related to pregnancy and requires prompt intervention. These patients should have a complete neurologic evaluation by a clinician experienced in this examination. A reasonable approach is illustrated by the following algorithm (algorithm 1) and discussed in detail separately (see "Evaluation of headache in adults"). Cerebral venous thrombosis and stroke are examples of disorders that are more common in pregnant/postpartum patients. (See "Cerebrovascular disorders complicating pregnancy".)

●Headache with altered mental status, seizures, papilledema, changes in vision, stiff neck, or focal neurological signs/symptoms

●Sudden onset of severe headache

●New-onset of migraine-type headache (eg, unilateral, throbbing or pulsatile quality with nausea, vomiting, photophobia or phonophobia)

●Headache in an immunosuppressed individual

●Change in headache characteristics (eg, pain, pattern, severity) from usual headaches

●Headache associated with/precipitated by fever, head trauma, illicit drug use or toxic exposure, cough, exertion, sexual activity, or Valsalva maneuver

●Headache of new onset that awakens the patient from sleep

●Headache unrelieved by pain medication

General approach to evaluating headache in pregnancy — Most pregnant patients with primary headache syndromes (tension-type headache, migraine headache, cluster headache) have been diagnosed before pregnancy [2]. A patient with a prior history of headache may continue to experience headache during pregnancy; pursuing a complicated duplication of diagnostic testing is not necessary if their characteristic symptoms have not changed and preeclampsia has been excluded.

Among pregnant patients with the onset of new or atypical headache in whom preeclampsia has been excluded, approximately half have migraine and the other half have a variety of other causes of headache (table 2) [8,9]. These patients should be evaluated initially with a detailed history and physical examination [10]. The diagnostic evaluation is similar to that in nonpregnant adults (see "Evaluation of headache in adults"), and should be initiated promptly in those with signs/symptoms of a serious underlying disorder. (See 'Patients with symptoms potentially associated with a serious underlying disorder' above.)

Migraine, tension-type, and cluster headaches are diagnosed by specific clinical criteria (table 3).

●(See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)

●(See "Tension-type headache in adults: Etiology, clinical features, and diagnosis".)

●(See "Cluster headache: Epidemiology, clinical features, and diagnosis".)

A general approach to the evaluation of new headache is shown in the algorithm (algorithm 2). Clinical features of headaches related to underlying conditions are described in the table (table 4).

Evaluation of postpartum patients — The postpartum period is characterized by hormonal and other physiological changes, sleep deprivation, irregular food intake, psychological stress, and fatigue. In addition, many patients have had a neuraxial anesthetic for labor and delivery or have been given vasoactive drugs (eg, ergots). These are all risk factors for development of headache. The following basic guidelines apply to the evaluation of patients with postpartum headache [11,12]:

●Preeclampsia should be the initial consideration in patients with hypertension. Preeclampsia can present postpartum, usually within 48 hours of delivery, but sometimes a week or more postpartum. (See 'Patients ≥20 weeks of gestation (evaluate for preeclampsia)' above.)

●The presence of worrisome signs/symptoms, such as new focal neurologic findings, warrants consultation with a neurologist. (See "Cerebrovascular disorders complicating pregnancy".)

●If the patient is normotensive and had neuraxial anesthesia for labor/delivery, an anesthesiologist or neurologist should be consulted for evaluation and treatment of postdural puncture headache (PDPH). The pain in PDPH typically develops within 48 hours of the procedure and is worse on standing or raising the head from the bed and characteristically improves with rest in a supine position; tinnitus, nausea, vomiting, and cranial nerve dysfunction rarely occur. (See "Post dural puncture headache".)

●Tension-type headache is the likely diagnosis in patients without focal neurologic deficits or findings consistent with preeclampsia. Migraine headache with or without aura is also common in this setting, especially in patients with a history of migraine (see 'Migraine' below and 'Tension-type headache' below). Cluster headache is rare (see 'Cluster headache' below). These headaches are diagnosed according to standard criteria from the International Classification for Headache Disorders (ICHD) (table 3).

Although headache is common postpartum, the prevalence across studies varies widely depending on the definitions used, method of ascertainment (eg, discharge diagnosis, postal survey, patient evaluation), timing (two to four days postpartum to one year after delivery), and patient population (eg, breastfeeding status).

The range and frequency of etiologies in different postpartum populations is illustrated by the following examples:

●In a prospective cohort study in which most of the 381 postpartum patients had mild or moderate headache pain, the most common etiologies were tension-type, migraine, and musculoskeletal/cervicogenic [11].

●In a retrospective study of 95 postpartum patients with severe unrelenting headache greater than 24 hours and less than 42 days from the time of delivery, the types and frequencies of headache were tension-type (39 percent), preeclampsia/eclampsia (24 percent), postdural puncture (16 percent), migraine (11 percent), pituitary hemorrhage/mass (3 percent), cerebral venous thrombosis (3 percent), and other (4 percent) [12].

●In a retrospective review of 63 consecutive postpartum patients who presented to the obstetric or emergency service with acute postpartum headache and were seen in consultation by the neurology service, 27 percent (17/63) had a primary headache disorder (most commonly migraine [13]) and 73 percent (46/63) had a secondary headache disorder (postdural puncture headache [21], preeclampsia [12], pituitary apoplexy [2], cerebral venous thrombosis [1], Moyamoya [1], RCVS [3], posterior reversible encephalopathy syndrome (PRES)[2], vertebral artery dissection [1], medication related headache [2], anemia related headache [1]) [13].

Imaging and lumbar puncture: Indications and safety — Indications for neuroimaging and lumbar puncture are similar to those in nonpregnant adults. (See "Evaluation of headache in adults", section on 'Indications for imaging' and "Evaluation of headache in adults", section on 'Lumbar puncture'.)

The choice of imaging modality should be determined by the suspected pathology, with the following considerations:

●Magnetic resonance imaging (MRI) does not expose the fetus to ionizing radiation and has not been associated with adverse fetal effects. Use of gadolinium should be avoided unless its use significantly improves diagnostic performance and is likely to improve patient outcome, as gadolinium may have adverse effects on offspring. (See "Diagnostic imaging in pregnant and lactating patients", section on 'Magnetic resonance imaging'.)

●Computed tomography (CT) involves ionizing radiation, but fetal radiation exposure from scatter is minimal during maternal head CT [14]. Iodinated contrast materials cross the placenta and can produce transient effects on the developing fetal thyroid gland; however, clinical sequelae from brief exposures have not been reported. Iodinated contrast materials should be used in pregnancy, when clinically indicated. (See "Diagnostic imaging in pregnant and lactating patients", section on 'Fetal risks' and "Diagnostic imaging in pregnant and lactating patients", section on 'Use of iodinated contrast materials'.)

Lumbar puncture is not contraindicated during pregnancy and should be performed following neuroimaging if increased intracranial pressure or infection is suspected. Neuroimaging is performed to exclude the presence of a large space-occupying lesion, which would be a contraindication to performing a lumbar puncture in the setting of increased intracranial pressure. (See "Lumbar puncture: Technique, contraindications, and complications in adults" and "Cerebrospinal fluid: Physiology and utility of an examination in disease states".)

APPROACH TO TREATMENT

General principles

●Treatment of headaches is indicated for maternal comfort. No large trials of headache therapy in pregnancy are available to provide data on which to base therapeutic recommendations. The major consideration is to "do no harm" since headaches do not appear to adversely affect pregnancy outcome [15-17].

●Drugs known to be teratogenic or otherwise potentially harmful in pregnancy (eg, uterotonic agents, vasoconstrictors) should be avoided. After exclusion of these drugs, treatment decisions are made according to recommendations for nonpregnant adults, but choosing those drugs with the best safety profile for the fetus and limiting the number of medications and doses to the minimum needed to control symptoms adequately. Treatment is also guided by the woman's prior treatment successes and failures, comorbid conditions, and gestational age (first trimester [ie, after the major period of organogenesis] versus later in pregnancy).

●Patients should have realistic expectations regarding the limits of therapy, and clinicians should be willing to treat headache pain aggressively when the patients requests aggressive treatment after a discussion of the available information about potential fetal risks.

Patients with preeclampsia — The definitive treatment of preeclampsia is delivery to prevent development of maternal or fetal complications from disease progression. Antihypertensive therapy should be initiated to reduce severe blood pressure elevation and prevent stroke. Magnesium sulfate is administered to prevent a first or recurrent eclamptic seizures. Preeclampsia-related headache can usually be relieved with acetaminophen. (See "Treatment of hypertension in pregnant and postpartum patients" and "Eclampsia", section on 'Prevention of recurrent seizures' and "Preeclampsia: Intrapartum and postpartum management and long-term prognosis", section on 'Seizure prophylaxis'.)

Postpartum patients — Non-breastfeeding postpartum patients are treated with the same drugs as nonpregnant adults, guided by the underlying cause of the headache.

In breastfeeding patients, medications that are transferred into breast milk and considered potentially harmful to the infant are avoided (eg, in the nursing infant, ergotamine may cause vomiting, diarrhea, weakness, and unstable blood pressure, and codeine may cause central nervous system depression). The American College of Obstetricians and Gynecologists advises a shared decision-making model regarding the need to avoid breastfeeding for a specified timeframe after use of triptans (8 to 12 hours after sumatriptan use and 24 hours after use of other triptans) and recommends against use of combination products containing butalbital, medications containing opioids (codeine, hydrocodone, oxycodone, hydromorphone), and ergot alkaloids [18].

The safety of medication use in breastfeeding mothers can be checked by searching on the drug name in the UpToDate drug information database or by searching on the drug name in other resources, such as LactMed.

Postdural puncture headache — Postdural puncture headache is often treated with a blood patch; breastfeeding is not a contraindication. Prophylactic epidural blood patch after unintentional dural puncture has been performed for the prevention of postdural puncture headache. (See "Post dural puncture headache", section on 'Treatment'.)

MIGRAINE

General considerations — Migraine is often, but not always, unilateral and tends to have a throbbing or pulsatile quality. Accompanying features may include nausea, vomiting, and photophobia or phonophobia during attacks. Triggering factors include stress, visual stimuli, weather changes, nitrates, fasting, sleep disturbances, and certain foods. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Clinical features' and "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Diagnosis'.)

Approximately 18 percent of females in the United States suffer from migraine headaches; many others have mild to moderate interference with their usual activities [19]. The prevalence of migraine in females peaks during the childbearing years. Approximately 2 percent of females develop their first migraine during pregnancy, usually in the first trimester [20].

A migraine occurring during pregnancy can generally be differentiated from a preeclampsia-related headache by assessment of the patient's blood pressure, urine protein, laboratory studies, gestational age, and whether she reports similar headaches prior to pregnancy. (See 'Patients ≥20 weeks of gestation (evaluate for preeclampsia)' above.)

Course in pregnancy — The occurrence of migraine is modulated by fluctuations in estrogen levels (see "Estrogen-associated migraine headache, including menstrual migraine", section on 'Pathophysiology of estrogen impacting migraine headache'). Most patients (60 to 70 percent) with a history of migraine report improvement over the course of pregnancy, approximately 5 percent describe worsening, and the remainder report no change [15]. Improvement is most likely in those with menstrual migraine, migraine without aura, and patients who experience improvement in the first trimester [15]. Improvement has been defined as absence of attacks, less severe attacks, decreased frequency of attacks, or shorter duration of symptoms.

The most common time for recurrence is postpartum. Patients with menstrual migraine are most likely to experience postpartum migraine, and those who breastfeed are less likely to experience migraine postpartum [21-24]. In a study of 49 postpartum patients with a history of migraine, migraine recurred during the first week postpartum in 34 percent and during the first postpartum month in 55 percent [21]. The prevalence of migraine in patients who breastfed and bottle-fed was 43 and 100 percent, respectively. The protective effect of breastfeeding, which has also been observed in other studies [25], has been attributed to more stable levels of estrogen in these individuals [15].

There appears to be an increased risk of stroke associated with migraine, particularly in patients who have migraine with aura. Stroke is also more common postpartum than during a six-week interval in a comparably aged nonpregnant adult female [26,27]. In a study that used discharge codes to evaluate risk factors for stroke in pregnancy and the puerperium, there appeared to be a strong association (odds ratio [OR] 16) between migraine and pregnancy/postpartum stroke [28,29]. The strong association may reflect the increased likelihood of accurately coding migraine in patients who have had a stroke and in the minority of patients whose migraines have been particularly active during pregnancy or postpartum. (See "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Female sex' and "Cerebrovascular disorders complicating pregnancy".)

Pregnancy outcome — Studies evaluating pregnancy outcome in migraineurs generally conclude that migraines, treated or untreated, are associated with an increased prevalence of hypertensive disorders of pregnancy [30-32]. As an example, in a nationwide, population-based cohort study comparing nearly 23,000 gravid patients with migraines with over 228,000 matched controls, migraine was associated with a 50 percent increase in the adjusted prevalence ratio for hypertensive disorders of pregnancy [30]. Miscarriage, preterm birth, and low birth weight were more modestly increased, and no increase in growth restriction or congenital anomalies was observed. Offspring had a disproportionate increase in short-term morbidities including admission to the neonatal intensive care unit and respiratory distress syndrome, as well as an increase in febrile seizures and epilepsy that persisted during the first year of life. Of note, patients with migraines had higher preconception levels of hypertension, depression, and asthma. (See "Preeclampsia: Clinical features and diagnosis" and "Gestational hypertension".)

The Nurses' Health Study included over 30,000 incident pregnancies among over 19,000 individuals of whom 2234 had self-reported physician-diagnosed migraine before pregnancy [32]. In this study, migraine was associated with a 40 percent higher risk of preeclampsia (term more than preterm) and a 28 percent higher risk of gestational hypertension compared with no migraine, after adjustment for multiple confounders, and migraine with aura increased the risk more than migraine without aura. Migraine was also associated with a 17 percent increase in preterm birth that persisted when only normotensive pregnancies were analyzed, but not associated with an increased risk of gestational diabetes.

Acute migraine treatment — The treatment of migraine in pregnancy differs somewhat from treatment of nonpregnant females because of concerns about adverse fetal drug effects. We begin with acetaminophen because it has the best maternal-fetal safety profile. If ineffective, we move on to other drugs in the order listed below. Patients with migraine that has not responded to oral drugs after several days should be evaluated for provoking factors and treated more aggressively. (See "Acute treatment of migraine in adults".)

First-line therapy: Acetaminophen alone or combination therapy — We initiate therapy with acetaminophen. Acetaminophen (1000 mg orally) can be an effective treatment of migraine [33], and data from large case series show no clear evidence of an increased risk of adverse effects on pregnancy or the fetus. These data are reviewed separately (see "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Acetaminophen'). Non-oral preparations are available.

Migraine that does not respond to acetaminophen alone may be relieved with oral combination therapy such as:

●Acetaminophen 650 to 1000 mg and metoclopramide 10 mg

●Acetaminophen-codeine (various formulations are available)

●Butalbital-acetaminophen-caffeine (various formulations are available)

Butalbital should be limited to only four to five days per month and codeine to no more than nine days per month to avoid development of medication overuse headache. The American College of Obstetricians and Gynecologists advises against the use of butalbital during pregnancy due to inconclusive data with regards to risk of teratogenicity and neonatal addiction; however, in practice, we have found the combination of butalbital-acetaminophen-caffeine to be quite effective in the treatment of refractory migraine if acetaminophen alone is not successful in resolving the headache. Its use in the first trimester should be discussed with shared decision-making.

These medications are generally safe for the fetus.

●Caffeine doses in medications for migraine range from 40 to 50 mg; daily caffeine intake less than 200 mg from all sources is unlikely to be associated with adverse pregnancy effects. (See "Caffeine: Effects on reproductive outcomes in females", section on 'Effects of caffeine on reproductive outcomes'.)

●Prolonged use of butalbital or codeine near term can cause neonatal withdrawal [34]. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes".)

●Prolonged use of barbiturates can cause vitamin K responsive bleeding in the neonate, but prophylactic vitamin K1 (phytonadione) is routinely given to all newborns in the United States shortly after birth to prevent vitamin K deficient bleeding. Butalbital has not been associated with an increased risk of congenital anomalies.

●The safety of short-term opioid use in the first trimester is unclear. Limited epidemiologic data have shown an association with nervous system malformations in offspring. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Opioids'.)

Second-line therapy: Aspirin or nonsteroidal anti-inflammatory drugs — Aspirin and nonsteroidal anti-inflammatory drugs, such as naproxen, ibuprofen, diclofenac, and ketorolac, are second-line options and are safest in the second trimester before 20 weeks. Non-oral preparations are available (eg, ketorolac 30 mg intravenously once). In the first trimester, a possible modest increase in early pregnancy loss and some congenital anomalies has been suggested, but available evidence is limited and weak. From 20 to approximately 30 weeks, fetal renal effects leading to oligohydramnios are a concern, generally after days to weeks of treatment; treatment <48 hours is generally safe. After 30 weeks, use should be avoided or limited to fewer than 48 hours due to concerns about prenatal constriction of the ductus arteriosus, persistent pulmonary hypertension of the newborn, oligohydramnios and its sequelae, necrotizing enterocolitis, renal dysfunction or failure, and intracranial hemorrhage. (See "Inhibition of acute preterm labor", section on 'Fetal side effects' and "Safety of rheumatic disease medication use during pregnancy and lactation".)

Third-line therapies

Opioids — Opioids (eg, oxycodone, hydromorphone, hydrocodone, meperidine, morphine) are a third-tier option. If used, use of all opioids should be limited to the lowest effective dose and prescribed for the shortest time required to control acute pain. These drugs should not be used on a chronic basis since they are addictive and can contribute to the development of medication overuse and chronic daily headaches [35,36]. They may also worsen the nausea/vomiting and constipation associated with pregnancy. All opioids have potential for maternal addiction and neonatal withdrawal. As discussed above, limited epidemiologic data have shown an association with nervous system malformations in offspring.

In postpartum breastfeeding patients, an additional consideration is that alterations in metabolism of some drugs (eg, codeine, tramadol) can occur due to genetic variations in cytochrome CYP2D6. This can result in high serum metabolite levels (ultrarapid metabolizers) with potential transfer of these active metabolites into maternal milk, causing excessive infant sedation and fatal overdoses in extreme cases. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Opioids' and "Overview of the postpartum period: Normal physiology and routine maternal care", section on 'Safety of common analgesics in breastfeeding individuals'.)

Triptans — For moderate to severe symptoms in patients who do not respond to other drugs, triptans can be considered [37]. Sumatriptan (50 to 100 mg orally, 4 to 6 mg subcutaneously, or 5 to 20 mg intranasal solution) and rizatriptan are two selective serotonin agonists that are highly effective in treating migraine headaches. They selectively vasoconstrict brain vessels, but there is a theoretic possibility of vasoconstriction of uteroplacental vessels and increased uterotonic activity [38]. Other triptans can also be used, but frovatriptan and naratriptan are less desirable than other triptans because of their longer half-life, and naratriptan is the least effective triptan. Preparations and dosing are discussed in more detail separately. (See "Acute treatment of migraine in adults", section on 'Triptans'.)

Human experience with triptan exposure during pregnancy primarily involves sumatriptan and has been generally reassuring [34,39,40]. A manufacturer's pregnancy registry for sumatriptan exposure during pregnancy did not find an increased risk of congenital anomalies or early pregnancy loss in 600 exposed pregnant patients, including 514 first-trimester exposures [34]. The pregnancy registry was closed in 2012; additional information may be obtained from the manufacturer (800-336-2176). In a 2015 systematic review of pregnancy outcome following prenatal exposure to triptans (6 studies, 4208 infants), triptan-exposed migraineurs had similar rates of major congenital anomalies, preterm birth, and early pregnancy loss as migraineurs not using triptans [39]. When the triptan-exposed group was compared with the healthy controls, rates of major congenital anomalies and preterm birth were similar, but early pregnancy loss was increased.

Drugs to reduce nausea and vomiting — The H1 antagonists meclizine (25 mg orally), diphenhydramine (25 to 50 mg orally or 10 to 50 mg intravenously), and promethazine (12.5 to 25 mg orally, per rectum, or intramuscularly) are preferred in pregnancy to relieve nausea and vomiting associated with migraine or migraine therapy.

Dopamine antagonists such as metoclopramide (10 mg intravenously, intramuscularly, or orally) or phenothiazines such as prochlorperazine (10 mg intravenously, intramuscularly, or orally) or chlorpromazine (25 to 50 mg intramuscularly) are effective, but maternal acute dystonic reactions sometimes occur.

As an alternative, ondansetron (4 to 8 mg orally or intravenously), a 5HT3 antagonist, may be used to treat severe nausea and vomiting associated with severe migraine headaches.

The safety profiles of all of these drugs and other anti-emetics used in pregnancy are reviewed separately. (See "Nausea and vomiting of pregnancy: Treatment and outcome".)

Drugs to avoid

●Ergotamine is absolutely contraindicated during pregnancy because of the potential to induce hypertonic uterine contractions and vasospasm/vasoconstriction, which could cause adverse fetal effects. Postpartum use is reasonable; contraindications are the same as for nonpregnant adults (eg, hypertension; concurrent use of protease inhibitors, azole antifungals, and some macrolide antibiotics).

●Isometheptene is a sympathomimetic amine that is used for relief of migraine and tension-type headaches. It is sold in combination with dichloralphenazone and acetaminophen. There is no information on its use in pregnancy and other alpha adrenergic agents have been shown to compromise uterine blood flow; therefore, it should be avoided.

Nonpharmacologic interventions — Nonpharmacologic interventions include heat, ice, massage, rest, avoiding triggers (eg, maintaining a regular meal and sleep pattern), and behavioral therapy (eg, relaxation training, biofeedback, cognitive behavioral therapy) [41]. (See "Preventive treatment of episodic migraine in adults", section on 'Lifestyle measures' and "Preventive treatment of episodic migraine in adults", section on 'Nonpharmacologic interventions' and "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Precipitating and exacerbating factors'.)

Refractory migraine treatment

First-line therapy — For management of severe, refractory migraine, our preference is a combination of intravenous hydration, an antiemetic (eg, prochlorperazine 10 mg), and an intravenous opioid [42,43]. We suggest pretreatment with 12.5 mg of diphenhydramine to avoid akathisia.

Second-line therapy — Combination therapy with a triptan and droperidol (2.5 mg intravenously every 30 minutes up to three doses) appears to be effective, but can be associated with extrapyramidal symptoms [44]. Droperidol has no proven teratogenic effects [34]; however, droperidol has been associated with maternal QTc prolongation and the development of torsades de pointes [45].

Third-line therapies

●Magnesium sulfate – The authors sometimes administer magnesium sulfate in the setting of refractory migraine given its safety in pregnancy and personal observations of clinical success. Although the safety of short courses (<5 consecutive days) of magnesium sulfate is well established in pregnancy, its efficacy for treatment of acute migraine in adults has not been clearly established, with conflicting findings among studies. In a 2014 meta-analysis of five randomized trials totaling 295 adults with acute migraine, magnesium treatment (1 or 2 g intravenously over 10 to 15 minutes) resulted in no statistically significant benefit in relief from headache or need for rescue analgesic medications compared with control patients receiving placebo, metoclopramide, or prochlorperazine [46]. However, the trials were underpowered to detect significant differences in these endpoints and generally of poor methodologic quality.

●Glucocorticoids – Glucocorticoids may be useful in intractable cases [47,48]. Prednisone (20 mg orally four times daily for two days) or methylprednisolone (4 mg orally, 21 tablets over six days) are the preferred glucocorticoids because they are metabolized to inactive forms by the placenta and thus have minimal fetal effects, whereas dexamethasone and betamethasone are metabolically active in the fetus [48]. Some older epidemiologic data suggest a possible association between first-trimester use of glucocorticoids and cleft lip and/or palate, while more recent data do not. (See "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate", section on 'Environmental factors'.)

●Peripheral nerve block – Peripheral nerve blocks may also be effective. In a series of 13 pregnant patients with migraine refractory to medication, injection of local anesthetic into one or more peripheral nerves (eg, occipital, auriculotemporal, supraorbital, supratrochlear) resulted in elimination of pain in seven, pain reduction in two, and no response in four [49]. Six patients received a single injection; the other seven received two to five sequential nerve blocks. There were no adverse maternal or fetal effects. In a randomized trial of 62 pregnant patients with headache and pain score >3 on the visual rating scale (VRS), occipital nerve block resulted in more patients with VRS scores ≤3 at one hour than standard care of acetaminophen and caffeine (58 versus 32 percent) and also increased the proportion of patients who left triage within one hour of the block as a result of headache resolution (58 versus 32 percent) [50]. Additional studies should be performed to better define the efficacy of this approach.

Preventive therapies — Patients with frequent migraine headaches often benefit from preventive therapy. The most common approach is daily use of beta blockers or calcium channel blockers in the lowest effective dose, and cognitive and behavioral therapy. Comanagement with a neurologist is essential in these difficult cases. The preventive treatment of migraine is reviewed in detail elsewhere (see "Preventive treatment of episodic migraine in adults"). Specific considerations relating to pregnancy are discussed below:

First-line preventive therapies:

●Beta blockers such as propranolol, metoprolol, and atenolol are not teratogens, but fetal/neonatal effects from beta blockade are possible with prolonged use and include mild fetal growth restriction and mild transient neonatal bradycardia, respiratory depression, hyperbilirubinemia, and/or hypoglycemia. Growth restriction may be more of an issue with atenolol than with other beta blockers. (See "Treatment of hypertension in pregnant and postpartum patients", section on 'Beta blockers'.)

●Short- and long-acting calcium channel blockers are commonly used for treatment of hypertension and preterm labor without adverse fetal/pregnancy effects. An increase in congenital anomalies has not been reported in humans, although information is limited [34]. Verapamil is the preferred agent because it is relatively safe and has good tolerability and ease of use. (See "Treatment of hypertension in pregnant and postpartum patients", section on 'Calcium channel blockers'.)

●Cyproheptadine is an older antihistamine agent sometimes used as a preventive therapy and does not appear to have adverse pregnancy effects.

Second-line preventive therapies:

●Low-dose antidepressants, such as the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine, or tricyclic antidepressants (TCA), may be considered in refractory patients, particularly those with suspected underlying chronic depressive illness or postpartum depression. Antidepressants have not been clearly associated with an increased risk of congenital anomalies, but can have neonatal effects when taken in the third trimester. The risks of these drugs in pregnant and breastfeeding patients are discussed separately. (See "Antenatal use of antidepressants and the potential risk of teratogenicity and adverse pregnancy outcomes: Selective serotonin reuptake inhibitors" and "Antenatal use of antidepressants and risks of teratogenicity and adverse pregnancy outcomes: Drugs other than selective serotonin reuptake inhibitors".)

●Gabapentin is an option for refractory patients. Some anticonvulsants, particularly valproate, are teratogenic and should be avoided [51]. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Choice of antiseizure medication'.)

Other:

●Although there are no studies reviewing their use in pregnancy, nutraceuticals may be considered for migraine prophylaxis. The most commonly used are magnesium 400 to 800 mg daily, riboflavin 400 mg daily, or extract of butterbur root 50 to 100 mg twice daily.

TENSION-TYPE HEADACHE

General considerations — Tension-type headaches are the most common type of headache. They are characterized by feelings of pressure or tightness all around the head, and have a tendency to wax and wane in intensity. Gastrointestinal upset and heightened sensitivity to light, sound, and smell may occur, but are more typical of migraine [52]. Tension-type headaches had been attributed to muscle aches from psychological stress. (See "Tension-type headache in adults: Etiology, clinical features, and diagnosis", section on 'Etiology'.)

Course in pregnancy — In contrast to migraine, the frequency of tension-type headaches usually does not change during pregnancy since these headaches are not hormonally mediated. In two small studies, 56 and 67 percent of patients reported no change in tension headache frequency during pregnancy, 40 and 28 percent reported improvement, and 4 and 5 percent reported worsening [53,54].

Pregnancy outcome — The only study that evaluated pregnancy outcome in patients with tension-type headache reported an increased risk of preterm birth (8.7 versus 2.8 percent in controls without headache), but this was likely due to chance given the unusually low rate of preterm birth in the control group [55].

Drug treatment — The acute treatment of tension-type headache in adults is similar in pregnant and nonpregnant patients, and is discussed in detail separately. (See "Tension-type headache in adults: Acute treatment".)

●First- and second-line therapies – Acetaminophen is the first-line analgesic for treatment of tension-type headaches during pregnancy, and a short course of nonsteroidal anti-inflammatory drugs (NSAIDs) is a second-line medical therapy, with the caveats described above. (See 'First-line therapy: Acetaminophen alone or combination therapy' above and 'Second-line therapy: Aspirin or nonsteroidal anti-inflammatory drugs' above.)

●Third-line therapies – If monotherapy is ineffective, a combination of acetaminophen 500 mg and caffeine 100 mg is a reasonable third tier.

Butalbital and codeine may be considered when other drugs have been ineffective or NSAIDs are contraindicated (eg, the third trimester of pregnancy), but prolonged use should be avoided due to the potential for drug dependency and medication overuse headaches. Butalbital should be limited to only four to five days per month and codeine to no more than nine days per month to avoid development of medication overuse headaches.

Nonpharmacologic interventions — Nonpharmacologic interventions include heat, ice, massage, rest, avoiding triggers (eg, maintaining a regular meal and sleep pattern), and behavioral therapy (eg, relaxation training, biofeedback, cognitive behavioral therapy) [41]. Physical therapy also may reduce the frequency of headaches in some patients.

CLUSTER HEADACHE

General considerations — Cluster headache is a repetitive headache that occurs for weeks to months at a time, followed by periods of remission. The pain begins quickly, reaches a crescendo within a few minutes, and is usually excruciating. It is always unilateral and associated with cranial autonomic symptoms, such as nasal stuffiness, lacrimation, facial sweating, or eyelid edema. (See "Cluster headache: Epidemiology, clinical features, and diagnosis".)

Course in pregnancy — Cluster headache is probably not affected by reproductive hormonal changes [56-58]. In a study that examined the clinical features of headache and the physiologic events related to reproductive life in 82 females with these headaches compared with a control group, the course of cluster headache was not altered by menstruation, pregnancy, or the puerperium [56]. However, other studies have reported improvement. In one such study, 6 of 8 females with a history of cluster headache who became pregnant reported remission during their 9 pregnancies [59] and another noted that 3 of 58 females with a history of cluster headache commented that they were due for a bout of headaches when they became pregnant, but missed the bout [60]. In one subject, the bout started postpartum after two pregnancies.

Pregnancy outcome — The effect of cluster headache on pregnancy outcome has not been described.

Treatment

First- and second-line therapies — First- and second-line therapies (oxygen, triptans) are similar to those in nonpregnant adults [61,62]. (See "Cluster headache: Treatment and prognosis".)

Abortive therapy of cluster headache can be difficult because of the short duration of each episode. In most patients, acute cluster headache can be aborted by inhalation of 100 percent oxygen. If unsuccessful, subcutaneous or intranasal sumatriptan is a reasonable option. As discussed above (see 'Triptans' above), human experience with sumatriptan exposure in several hundred pregnancies has been reassuring.

Topical lidocaine — If response to these therapies is suboptimal, 0.5 mL lidocaine 4% can be placed inside the nostril on the affected side of the head; extensive experience with local anesthesia in pregnancy suggests that it is not associated with significant adverse reproductive or teratogenic effects [34].

Drugs to avoid — Ergotamine is effective but absolutely contraindicated during pregnancy because of the potential to induce hypertonic uterine contractions and vasospasm/vasoconstriction, which could cause adverse fetal effects. Postpartum use in non-breastfeeding patients is reasonable; contraindications are the same as for nonpregnant adults (eg, hypertension; concurrent use of protease inhibitors, azole antifungals, and some macrolide antibiotics). Because of limited published experience with ergotamine during breastfeeding and the potential for adverse effects in the infant, we avoid its use in nursing patients.

Preventive therapy

First-line therapies — When preventive therapy is indicated, the two best options during pregnancy are verapamil and glucocorticoids [61].

Verapamil is the preferred calcium channel blocker because it is relatively safe and has good tolerability and ease of use. The starting dose is usually 240 mg daily in three divided doses. Most patients respond to a total dose of 240 to 320 mg daily. Titration to a total dose of up to 960 mg daily may be necessary for some patients to obtain full prophylactic benefit (see "Cluster headache: Treatment and prognosis", section on 'Verapamil plus glucocorticoids for patients with frequent attacks'). As discussed above, short- and long-acting calcium channel blockers are commonly used for treatment of hypertension and preterm labor, without adverse fetal/pregnancy effects. An increase in congenital anomalies has not been reported in humans, although information is limited [34].

Prednisone (20 mg orally four times daily for two days) and methylprednisolone (4 mg orally, 21 tablets over six days) are the preferred glucocorticoids because they are metabolized to inactive forms by the placenta and have minimal fetal effects, whereas dexamethasone and betamethasone are metabolically active in the fetus [48]. Some older epidemiologic data suggest a possible association between first-trimester use of glucocorticoids and cleft lip and/or palate, while more recent data do not. (See "Cluster headache: Treatment and prognosis", section on 'Glucocorticoids for patients with infrequent attacks' and "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate", section on 'Environmental factors'.)

Second-line therapies — After the first trimester, lithium and topiramate are options. (See "Cluster headache: Treatment and prognosis", section on 'Lithium' and "Cluster headache: Treatment and prognosis", section on 'Topiramate'.)

First-trimester fetal exposure to lithium has been associated with Ebstein's anomaly, and third-trimester exposure has been associated with signs of lithium toxicity in neonates. (See "Teratogenicity, pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Lithium'.)

First-trimester exposure to topiramate has been associated with cleft lip and/or palate, so use of the drug should be avoided before anatomic closure (complete closure of the lip is usually accomplished by 35 days postconception and palatal closure is complete by 56 to 58 days postconception) [34]. Use of topiramate during pregnancy has also been associated with low birth weight [63,64]. (See "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Topiramate'.)

Third-line therapies — Third-line agents include pizotifen, gabapentin, intranasal application of capsaicin, oral melatonin [61], and greater occipital nerve block. Pizotifen and gabapentin should not be used in the first trimester because there is only sparse information on fetal effects of gabapentin and pizotifen [34]. There is minimal information on use of capsaicin and melatonin in pregnancy, but short-term use is unlikely to be harmful. (See "Teratogenicity, pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Lithium' and "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Effects of ASMs on the fetus and child' and "Cluster headache: Treatment and prognosis", section on 'Other medications'.)

MEDICATION OVERUSE HEADACHE — Medication overuse headaches may develop with frequent (daily) use of analgesics, including acetaminophen, in patients with recurrent headaches. Medication overuse headaches may be confused with migraine and can develop in patients with migraine; the diagnosis should be suspected in patients who have persistent daily headaches despite the regular use of analgesic medications. The only treatment is cessation of the offending drug. (See "Medication overuse headache: Etiology, clinical features, and diagnosis" and "Medication overuse headache: Treatment and prognosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine and other primary headache disorders".)

SUMMARY AND RECOMMENDATIONS

●Patients requiring urgent evaluation – Preeclampsia (table 1) must be ruled in or out in every pregnant woman over 20 weeks of gestation or postpartum with headache. (See 'Patients ≥20 weeks of gestation (evaluate for preeclampsia)' above.)

Pregnant patients with headache characteristics that may be associated with a serious underlying disorder (table 5), especially if not typical of the patient's usual headache, should be evaluated immediately for an acute neurovascular event (algorithm 1), as well as preeclampsia. (See 'Patients with symptoms potentially associated with a serious underlying disorder' above.)

●General approach to evaluation

•A patient with a prior history of tension-type headache, migraine headache, or cluster headache may continue to experience headache during pregnancy; pursuing a complicated duplication of diagnostic testing is not necessary if their characteristic symptoms (table 3) have not changed and preeclampsia has been excluded. (See 'General approach to evaluating headache in pregnancy' above.)

•Among pregnant patients with the onset of new or atypical headache in whom preeclampsia has been excluded, approximately half have migraine and the other half have a variety of other causes of headache (table 2). These women should be evaluated initially with a detailed history and physical examination, similar to that in nonpregnant adults. A general approach to the evaluation of new headache is shown in the algorithm (algorithm 2). Clinical features of headaches related to underlying conditions are described in the table (table 4). (See 'General approach to evaluating headache in pregnancy' above.)

•Indications for neuroimaging and lumbar puncture are similar to those in nonpregnant adults. If magnetic resonance imaging is performed, use of gadolinium should be avoided as it appears to have adverse effects on offspring. If computed tomography of the head is performed, fetal radiation exposure from scatter is minimal. (See 'Imaging and lumbar puncture: Indications and safety' above.)

●Treatment during pregnancy

•Migraine – Most patients with migraine headache report improvement during pregnancy. For women who request drug therapy, we suggest acetaminophen as first-line acute (abortive) therapy (Grade 2C). For patients who do not respond to acetaminophen alone, we suggest acetaminophen combination therapy (Grade 2C). Oral drug options include acetaminophen (650 to 1000 mg) and metoclopramide (10 mg); acetaminophen-codeine; or butalbital-acetaminophen-caffeine.

If unsuccessful, our second-line approach is a nonsteroidal anti-inflammatory drug for <48 hours, followed by third-line options, beginning with an opioid and then moving to sumatriptan if the opioid is unsuccessful or needed frequently. (See 'Acute migraine treatment' above.)

•Tension headache – The frequency of tension-type headache generally remains stable during pregnancy since it is not hormonally mediated. We recommend acetaminophen as first-line drug therapy (Grade 1B). Nonpharmacologic/behavioral interventions are also useful. (See 'Tension-type headache' above.)

•Cluster headache – The frequency of cluster headache generally remains stable during pregnancy, since it is not hormonally mediated. In most patients, acute cluster headache can be aborted by inhalation of 100 percent oxygen. If unsuccessful, subcutaneous or intranasal sumatriptan is a reasonable option. (See 'Cluster headache' above.)

●Postpartum patients – The postpartum period is characterized by multiple changes that increase the risk of developing headache. Differential diagnosis includes primary headache (almost always tension-type or migraine) and secondary causes of headache, including preeclampsia/eclampsia, postdural puncture headache, and cerebral venous thrombosis. The presence of focal neurologic signs usually requires neurologic imaging and consultation with a neurologist to rule out intracranial pathology. (See 'Evaluation of postpartum patients' above.)