Migraines In Women
From Handbook of Headache; by Randolph W. Evans, MD, advisor to MAGNUM.
Excerpt from Evans RW, Mathew NT, Handbook of Headache, Lippincott-Williams & Wilkins, Philadelphia, 2000, pp 139-149, 2000, with permission.
Women have headaches more commonly than men. The prevalence of migraine is 18% of women and 6% of men. This gender ratio increases from menarche, peaks at age 42, and then declines. For females, the incidence of migraine with aura peaks between ages 12 and 13 (14.1/1000 person-years) and migraine without aura between ages 14 and 17 (18.9/1000 person-years).(i) Table 1 provides the lifetime prevalence of various headaches in women and men.
Table 1. Lifetime prevalence of headaches in women and men
Estrogen levels are a key factor in the increased prevalence of migraine in women. Evidence includes the following: migraine prevalence increases at menarche; estrogen withdrawal during menstruation is a common migraine trigger; estrogen administration in oral contraceptives and hormone replacement therapy can trigger migraines; migraines typically decrease during the second and third trimesters of pregnancy when estrogen levels are high; migraines are common immediately post-partum with the precipitous drop in estrogen levels; and migraines generally improve with physiologic menopause. Exactly how changes in estrogen levels influences migraine is not understood. Among numerous effects, fluctuations in estrogen levels can result in changes in prostaglandins and the uterus, prolactin release, opioid regulation, and melatonin secretion. Changes in neurotransmitters including the catecholamines, noradrenaline, serotonin, dopamine, and endorphins.(ii)
This chapter will review some important headache issues for women including menstrual migraine, menopause and migraine, oral contraceptive use in migraineurs, and headaches during pregnancy and the postpartum.
Introduction. The reported prevalence of menstrual migraine varies from 4% to 73% depending upon the criteria used for the timing of the attack. MacGregor proposes the following definition: attacks of migraine without aura that occur regularly on day 1 of menstruation ▒ 2 days and at no other time.(iii) Using this definition, 7% of female migraineurs have only menstrual migraine. Menstruation is a trigger for about 60% of migraineurs. Symptoms of the premenstrual syndrome, which occurs during the luteal phase, include depression, anxiety, crying spells, difficulty thinking, lethargy, backache, breast tenderness, swelling, and nausea. Both migraine and tension type headaches can be associated.
Management. The symptomatic treatment is the same as for other migraines and include non-steroidal anti-inflammatory drugs, ergotamine, dihydroergotamine, and triptans. (Chapter 2). Triptans are just as effective for menstrual migraine. Women with frequent migraines including menstrual migraine may benefit from preventative treatment (Chapter 2). Increasing the dose perimenstrually can be helpful in some cases.
Table 2. Options for interval preventative treatment of menstrual migraine starting 2-3 days before and continuing during the menses
When menstrual migraine is the only migraine or the most severe and prolonged, a variety of short term preventative treatments may be effective starting 3 days premenstrually and continuing during the menses for women with regular cycles (Table 2). , Non-steroidal anti-inflammatory drugs (NSAID) can be especially helpful when migraine occurs with dysmenorrhea or menorrhagia.(vi) Some patients may respond to one class of NSAID and not another.
Hormonal treatments which may be effective include transdermal estradiol (Table 2), bromocriptine 2.5 mg three times a day (continuous treatment more effective than interval),(vii) danazol 200 mg two or three time a day, and tamoxifen 5-15 mg daily for days 7-14 of the luteal cycle (there are concerns about use because of an increased risk of uterine cancer).(viii) Some women may respond to a short tapering dose of corticosteroids or chlorpromazine 10 to 50 mg twice a day for 4 to 7 days. Oral magnesium (360 mg of magnesium pyrrolidone carboxylic acid) may also be effective.(ix) Hysterectomy is not recommended for the management of menstrual migraine.
MENOPAUSE AND MIGRAINES
Introduction. Two thirds of women with prior migraine improve with physiologic menopause. By contrast, surgical menopause results in worsening of migraine in two thirds of cases.
Estrogen replacement therapy. Hormone replacement therapy has a variable effect on migraine frequency: 45% improve, 46% worsen, and 9% are unchanged.(x) Table 3 provides changes in hormone replacement therapy which may be helpful when migraines increase. The usual abortive and prophylactic migraine medications can also be used (Chapter 2).Table 3. Treatment of estrogen replacement headache(xi)
ORAL CONTRACEPTIVE (OC) USE AND MIGRAINE
Influence on onset and frequency. Migraines may occur for the first time following OC use. The effect of OC use is quite variable: migraines may increase, decrease, or stay the same. Much of the data on this topic is from older studies of the use of high dose estrogen contraception which often increased migraine frequency. Low estrogen dose OCs usually have no effect or may improve migraine. When new onset migraine occurs or migraine frequency increases, perhaps 30-40% of this group will improve when OCs are discontinued. However, improvement may not occur for up to 1 year.
Risk of stroke.(xii) Since the 1970's, there has been concern that the use of OCs in migraineurs may increase the risk of stroke. Review of the risk of stroke in young women, female migraineurs, and from OC use helps to clarify this issue. Stroke in young women. The annual incidence of cerebral infarction in young women is low: about 4/100,000 for women aged 25-34 and 11/100,000 in women aged 35-44. For women who do not have migraine and do not take OCs, the annual incidence is perhaps 1.3/100,000 for women aged 25-34 and 3.6/100,000 for women aged 35-44. Hypertension, diabetes, cigarette smoking, and cocaine use are significant risk factors. Stroke and migraine. There is an increased risk of stroke in women with migraine.(xiii), (xiv) Using a variety of assumptions, Becker has calculated the approximate risk of stroke in young women not on OC with and without migraine.11
Stroke and use of OCs. This is a controversial topic because studies of low dose estrogens have yielded conflicting results. The risk of stroke associated with OCs may vary with the estrogen dose. Based upon numerous studies, OCs with different estrogen doses have an increased risk of thromboembolic stroke (odds ratio) as follows: more than 50 mg, 8-10; 50 mg, 2-4; and 30-40 mg, 1.5-2.5.2 However, recent studies have not shown an increased risk of stroke in women who use low estrogen dose OCs.(xi), (xvi), (xvii) OCs containing only progesterone do not increase the risk of stroke.(xvii)
Use of OCs in migraineurs. There is some evidence to suggest that OC use in migraineurs increases the risk of stroke. Tzourio et al reported the odds ratio (increase of relative risk) of ischemic stroke in young women using low estrogen dose OCs as follows: without migraine, 3.5 and, with migraine, 13.9.12 The significance of this finding is not certain in view of the more recent OC use and stroke studies showing no increased risk.
Most women with migraine without aura can safely take low-dose estrogen OCs when there are no other contraindications to OC use. Similarly, those with migraine with auras such as visual symptoms lasting less than 1 hour can also use OCs. Women with aura symptoms such as hemiparesis or dysphasia or prolonged focal neurological symptoms and signs lasting more than 1 hour might best avoid starting low-dose estrogen OCs and stop the medication if they are already taking it. In addition, the physician considers other factors in prescribing OCs such as older age, cigarette smoking, and comorbidity such as diabetes, uncontrolled hypertension, and coronary artery disease. Progesterone only OCs and the many other contraceptive options can be considered with the patient.
Table 4. Approximate incidence of ischemic stroke (strokes per 100,000 women per year) in women with and without migraine who do not use oral contraceptives
HEADACHES DURING PREGNANCY AND THE POSTPARTUM
Introduction. About 90% of headaches occurring during pregnancy and the postpartum are benign. The frequency of tension type headaches generally does not change. Migraine headaches usually occur less often. Management of frequent benign headaches can be challenging because restrictions on medication use. Life threatening causes of headache which can occur during this time include pre-eclampsia and eclampsia, subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral venous thrombosis. There are numerous other secondary causes including pseudotumor cerebri, brain tumors (including choriocarcinoma), and infections such as Listeria.
Neuroimaging.(xix) When there are appropriate indications (see Chapter 1), neuroimaging should be performed during pregnancy. With the use of lead shielding, a standard CAT scan of the head exposes the uterus to less than 1 mrad. A radiation dose of $15 rad is necessary to result in deformities that might justify pregnancy termination. CAT scan is the study of choice for the evaluation of head trauma or acute subarachnoid hemorrhage. MRI is more sensitive for disorders which may occur during pregnancy such as pituitary apoplexy, cerebral venous sinus thrombosis (with the addition of MR venography), and metastatic choriocarcinoma. There is no known risk of MRI during pregnancy but there is some controversy because the magnets induce an electric field and slightly raise the core temperature (less than 1E C.). Although there is no known risk of intravenous contrast for CAT scan or gadolinium for MRI, contrast should be avoided if possible. The radiation dose for a typical cervical or intracranial arteriogram is less than 1 mrad.
Migraine. Epidemiology. The new onset of migraine has been variably reported as occurring in 1% and 10% of migraineurs during pregnancy, usually during the first trimester. During pregnancy, pre-existing migraine improves or disappears in about 60%, has an unchanged frequency in 20%, and an increased frequency in 20%. Improvement often occurs during the second or third trimester. In one study, menstrual migraine disappeared or improved in 85% and worsened in 7% in contrast to nonmenstrual migraine which disappeared or improved in 60% and worsened in 15%.(xx) When improvement occurs with the first pregnancy, improvement also occurs during subsequent pregnancies in about 50% whereas an increased frequency occurs in the other 50%.(xxi) Migraineurs do not have an increased risk of miscarriages, toxemia, congenital anomalies, or stillbirth.
One study reported that 38% of women had headaches during the first postpartum week esepcially between days 3-6.(xxii) These headaches occurred more often in women with either a personal or family history of migraine. Many of the women described a mild to moderately severe bifrontal pain associated with photophobia and nausea. These headaches may be triggered by rapidly falling estrogen levels. In another study, 4.5% of women had the new onset of migraine during the postpartum period.(xxiii)
Management.(xxiv), (xxv), (xxvi), (xvii) Fortunately, migraines usually improve or disappear during pregnancy. Non-medication approaches include avoidance of triggers, ice, sleep, and biofeedback.
Before prescribing medication, the patient should be advised of the potential risk during pregnancy. For many drugs, there is insufficient knowledge about the risks of birth defects despite the fact that 67% of women take medications during pregnancy and 50% take them during the first trimester.(xxviii) The FDA drug risk ratings provide some guidance for medication use during pregnancy. If non-obstetricians (such as neurologists or internists) are managing the migraines, they should confer with the obstetrician about medication use.
SYMPTOMATIC MEDICATIONS. Many migraineurs want to take medication during pregnancy especially for moderate to severe migraines. Concerns include not only the potential of risk for the fetus, but also medication rebound headaches from overuse as well as habituation with the overuse of butalbital and narcotics. Acetaminophen, which is FDA Class B (no evidence of risk in humans, but there are no controlled human studies), is the medication of choice since there is no evidence of any teratogenic effect. Aspirin is rated Class C (risk to humans has not been ruled out) during the first and second trimesters and Class D (positive evidence of risk to humans from human or animal studies) during the third trimester. Although there is no definite evidence of teratogenicity, there are multiple possible adverse effects including the following: inhibition of uterine contraction; longer gestation and labor; increased maternal and newborn bleeding; narrowing of the ductus arteriosus; ; and hyperbilrubinemia. Low dose aspirin daily aspirin is generally safe when used to prevent preeclampsia or for the treatment of antiphospholipid antibody syndrome although there may be an increase risk of abruptio placentae.
Caffeine in small doses of less than 300 mg a day is Class B and probably safe. Although butalbital is Class C , there has been no evidence of an association with malformations. However, prolonged overuse can result in fetal dependence and severe neonatal withdrawal. If acetaminophen alone is not effective, some patients will benefit from the addition of butalbital (Phrenillin«) or butalbital and caffeine (Fioricet«) which can also be combined with codeine.
Codeine in reasonable amounts is probably safe. However, indiscriminate use of codeine (Class C) during the first and second trimesters has a potential for risk since defects such as cleft lip or palate and hip dislocation have been reported. Meperidine and methadone (both are Class B) and butorphanol (Class C) are probably not teratogenic.
Non-steroidal anti-inflammatory drugs such as ibuprofen and naproxen are Class B but should be avoided during the third trimester because of the potential of inhibiting labor, prolonging the length of the pregnancy, and decreasing amniotic fluid volume. There is also concern over the possibility of causing pulmonary hypertension or premature closure of the ductus arteriosus.
Ergotamine and dihydroergotamine (both Class X, contraindicated in pregnancy) should not be used during pregnancy although the actual risk is not clear. Triptans such as sumatriptan (Imitrex«) are Class C. Although there is no evidence of teratogenicity at this time, the use of triptans during pregnancy should be avoided. Antiemetics may be necessary if the headache is associated with prominent nausea or vomiting and their use may prevent dehydration which can pose a risk to both the mother and fetus. Prochlorperazine, promethazine, and chlorpromazine (available orally, parenterally, and by suppository) are all Class C and metoclopramide is Class B. These drugs are generally considered reasonably safe during pregnancy especially with occasional use. No congenital malformations have been reported with the use of metoclopramide.
Prolonged migraine may be treated with 10 mg of prochlorperaizine intravenously and IV fluids. The addition of parenteral narcotics may help some patients. Migraine status may respond to the administration of intravenous corticosteroids such as dexamethasone 4 mg IV.
PREVENTATIVE MEDICATIONS. Frequent severe migraines associated with nausea and vomiting may justify the use of preventative medications.
Valproic acid, which is Class D (positive evidence of risk to humans from human or animal studies), should be avoided because of the 1-2% risk of neural tube defects when taken between day 17 and 30 after fertilization.
ß-blockers, routinely used during pregnancy for the treatment of hypertension, are the preventative of choice if medical contraindications are not present. Atenolol, nadolol, propranolol, and timolol are Class C and metoprolol is Class B. Although there is no evidence of teratogenicity, there may be an increased incidence of small for gestatational age infants. Propanolol may cause fetal and neonatal toxicity.
Antidepressants might be considered in some cases. Tricyclic antidepressants such as amitriptyline and nortriptyline are Class D and doxepin and protriptyline are Class C. These drugs are associated with a low risk of harm to the fetus, if any. Tricyclics should be stopped at least 2 weeks before the due date. There are reports of infants with respiratory distress and feeding difficulties born to women who took tricyclics through delivery. Fluoxetine (Class B), a SSRI, is questionably effective for migraine prevention but there is evidence of efficacy for chronic daily headache. Use of fluoxetine might be considered in a patient with frequent headaches and depression.
Another option is the calcium channel blocker, verapamil (Class C), which is probably safe during pregnancy. This drug is preferable to ▀-blockers for prevention of migraine with prolonged aura. In addition, verapamil can also be considered in women with hypertension and frequent migraines who can not take ß-blockers.
Breastfeeding and migraine management. The American Academy of Pediatrics Committee on Drugs has made recommendations based upon their review of drug use during lactation (Table 5).(xxix) Ergotamine is contraindicated during breastfeeding. Drugs whose effect on nursing infants is unknown but may be of concern include antidepressants such as amitriptyline and fluoxetine. Their use is probably safe since there are no reported adverse effects.
Maternal medications usually compatible with breastfeeding include the following: acetaminophen; barbiturates (which may cause infant sedation); caffeine (which may cause irritability or poor sleeping pattern if the mother uses a lot of caffeine); non-steroidal anti-inflammatory drugs such as ibuprofen and naproxen; ß-blockers such as propranolol and nadolol; narcotics including codeine, morphine, and butorphanol; valproic acid; and verapamil. Triptans (which are not listed in the report) should be used with caution.
Table 5. Drug therapy in lactating women: questions and options
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