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Introduction
The term migraine originates from the Greek word hemicranias, which means "half of the head"1. Nevertheless, there are historical recordings of headaches dating back nearly 600 years. In the 17th century, a migraine was called a "hypoglycemic headache," and the term "chronic migraine was coined during the early 20th century"2.
Definition
Migraine is a chronic brain disease with episodic manifestations that typically involve unilateral headache of throbbing or pulsating quality, associated with complex sensory disturbances such as photophobia and phonophobia and neurovegetative symptoms such as nausea or vomiting. Migraine can occur in episodic or chronic forms, with or without aura1,3,4. An aura consists of focal neurological symptoms with positive and negative manifestations, most commonly visual disturbances. Approximately one-third of patients will report an associated aura with their migraine5.
Epidemiology
Migraine accounts for 20% of all outpatient neurology consultations6 and thus is considered the most common cause of disability worldwide7,8. Yearly, it affects one billion people worldwide9.
Migraine has racial disparities in its incidence, being more common among Caucasians1, in its episodic form, it affects nearly 12-18.5% of adult subjects. In contrast, chronic migraine affects ~2% of the general population4, particularly those younger than 506. There is also an apparent sex disparity among females in a proportion 1:2 or 1:3 (20.2% to 24.4% vs. 9.4%)4,5,10, but only in adults, in young childhood, the prevalence of migraine are marginally higher in boys than in girls. In contrast, in pre-pubertal populations, prevalence is similar among both genders. However, after menarche, migraine prevalence increases in girls (6.4%) compared with males (4.0%)11-13. The disparity in the incidence of migraine between men and women seems to be related to the hormonal differences between sexes; specifically, estrogens and progesterone appear to play a pivotal role in producing the disease14,15.
The incidence of migraine in women between 30 and 39 years (the central period of reproductive age) is 24%16. Migraine symptoms also vary due to other hormonal states, such as hormonal contraception, pregnancy, and menopause16-18. During the reproductive age, migraine prevalence becomes 3 times higher in women than men12. Then, after age 60, prevalence decreases in both sexes (5.0% women, 1.6% men)6.
The pathophysiologic mechanism by which menstruation favors the susceptibility to migraine attacks is not well understood, but sudden decreases in estrogen serum levels appear to be implicated. Still, similar drops in circulating estrogen during ovulation do not seem to provoke migraine attacks19.
Migraine in pregnancy
Nearly 60-80% of pregnant women with migraine will suffer attacks, which can be especially burdensome during the first trimester. After the first trimester has passed, about half of the patients will improve; by the last trimester, up to 80% will have improved16,20.
Two possible explanations exist for migraine symptoms decreasing after the first trimester of pregnancy. One is the physiological increase in estrogen and endogenous opioid levels, and the other is the disappearance of sudden fluctuation in hormone levels, a factor that usually triggers attacks16. Estrogens modulate neuronal excitability by upregulating serotonin, norepinephrine, dopamine, and endorphin levels and downregulating the endothelial nitric oxide synthase.
MacGregor and Hackshaw demonstrated that migraine attacks are more frequent during the late luteal and early follicular phase of falling estrogen; in contrast, attacks are less frequent during the increase of estrogen. Therefore, increased levels of estrogen protect women against migraine attacks21.
The phenotype of migraine might be modified in pregnant women20. One of the most common changes is aura development22. In a retrospective hospital-based study, 70% of women diagnosed with migraine with aura had no prior history of aura20.
Migraine without aura improves more frequently than other types of migraine during the first trimester; partial improvement is seen in 46.8% and remission in 10.6%. During the second trimester, remission rates increase to 53.2%, and in the third semester, the remission rate reaches 78.7%16. Pregnant migraineurs with aura also experience improvement in their symptoms. However, it is not as crucial as in women without aura.
Diagnosis
If the diagnosis of migraine does not precede the pregnancy, the International Classification of Headache Disorders, 3rd edition (beta version) (ICHD-3 beta)23 diagnostic criteria for migraine can be applied regardless of the pregnancy state24. However, excluding other causes of headache in this particular population is vital since, especially in low-income countries, pregnant women are at a heightened risk of cerebral venous thrombosis (CVT), pre-eclampsia/eclampsia and posterior reversible encephalopathy syndrome, among several grave secondary causes of headache25.
Differential diagnosis
There are several conditions that, such as migraine, also increase its frequency during pregnancy. The most important include26:
Idiopathic intracranial hypertension
It can appear during the first half of the pregnancy; its physiopathology is related to pregnancy-related weight gain. The headache is continuous, holo cranial, progressive, and aggravated by the Valsalva maneuver. Abnormalities in the neurological examination can include papilledema, visual disturbances, tinnitus, or paresis of the VI cranial nerve27.
Pre-eclampsia and eclampsia
It commonly occurs after the 20th week 20 of pregnancy and during the puerperium. The headache is bilateral, pulsatile, and aggravated by physical activity. Its course is toward progressive deterioration without response to symptomatic treatment until the end of pregnancy. Additional clinical features include significant visual disturbances, seizures, and confusion26.
Cerebral Venous Thrombosis
It can occur during any stage of pregnancy and puerperium. The headache is the most common presenting symptom. It tends to be paroxysmal, severe, and throbbing. It can be holocephalic or unilateral and have migraine-like features. Accompanying focal neurological symptoms include seizures, blurred vision, nausea, and vomiting28.
Central nervous system tumors
Although intracranial tumors do not have a higher incidence during pregnancy, tumors such as pituitary adenomas and meningiomas may grow during pregnancy. Therefore, the clinical presentation of brain tumors during pregnancy tends to occur in the second half of the pregnancy. Although headache is a common presenting feature of brain tumors, it is rarely its only manifestation, and focal neurological complaints and symptoms of increased intracranial pressure, such as nocturnal headache, nausea, vomiting, and blurred vision, are almost universally present29.
Treatment
Treatment for acute migraine should be tied to the severity of the headache. For mild-to-moderate headaches, treatment is initially based on first-line drugs. Paracetamol is safe during pregnancy. However, long-term use has been recently associated with hyperactivity and behavioral disorders30. Metoclopramide is also considered safe if nausea is prominent and concomitant to the pain.
Non-steroidal anti-inflammatories are possibly safe to take under certain circumstances but have also been associated with premature closure of the ductus arteriosus and pulmonary hypertension. Ibuprofen, diclofenac, naproxen, and piroxicam during the second trimester have also been associated with low birth weight. Ibuprofen during the second and third trimesters was associated with asthma. During the third trimester, diclofenac was related to maternal vaginal bleeding. Finally, indomethacin has been associated with miscarriage31.
Triptans are also classified as possibly safe to take during pregnancy but are mainly reserved for migraine with aura and severe migraine32. These 5-HT 1B/D agonists are safer during the first trimester of pregnancy. Still, during the second and third trimesters, a small association has been demonstrated between the risk of atonic uterus and post-delivery bleeding. Triptans are contraindicated in patients with poorly controlled hypertension, hemiplegic migraine, severe hepatic and renal impairment, basilar migraine, and coronary artery disease33.
Lasmiditan, a 5-HT 1F receptor antagonist, might be a safer alternative for acute migraine in pregnant women with cardiovascular conditions34. Onabotulinum toxin A has been used for chronic migraine in Europe1.
Calcitonin gene-related peptide (CGRP) antibodies monoclonal antibodies.
In recent years, the US FDA has approved CGRP monoclonal antibodies as a promising preventive treatment for migraine. Current options vary according to the route of administration and dose schedules and include erenumab, galcanezumab, fremanezumab, and eptinezumab35. Nevertheless, safety data on migraine preventive monoclonal antibodies targeting the CGRP system in pregnancy are limited36.
No specific maternal, fetal, or neonatal toxicity patterns were observed in a pharmacovigilance assessment of the safety reports related to pregnancy associated with erenumab, galcanezumab, fremanezumab, and eptinezumab. Spontaneous abortion was not more frequently reported with CGRP monoclonal antibodies compared with the use of other prophylactic drugs (ROR 1.1, 95% confidence interval, CI, 0.8-1.5), and triptans (ROR 1.2, 95% CI 0.8-1.9)33. However, a relatively limited number of adverse drug reactions are reported, and long-term safety data is lacking. Therefore, its use in pregnant women is anecdotal and case-by-case. In the event of prescription, continuous surveillance is required in pregnant and lactating women exposed to these drugs37. Table 1 lists medications' doses and risk class with documented use during pregnancy. Table 2 shows the risk classification system in pregnancy and breastfeeding.
Table 1 Doses and risk class of medications used in pregnant women with migraine
| Drug | Dose | Risk category |
|---|---|---|
| Aspirin | 325-650 mg, oral, or rectal q4h | First and second trimester: C Third trimester: D |
| Ibuprofen | 400 mg tablets 400-800 mg q3h, oral; maximum dose: 2400 mg/day |
First and second trimester: B Third trimester: D |
| Diclofenac | 100-200 mg tablets 75 mg, q12h, and oral 50 mg, q8h, and oral 100 mg, q12h, and oral |
First and second trimester: B Third trimester: D |
| Naproxen | 500/825 mg, oral | First and second trimester: B Third trimester: D |
| Ketorolac | Oral: 2 tablets q6h Intramuscular: 60 mg/2 mL; repeat in 4 h if needed | First and second trimester: B Third trimester: D |
| Acetaminophen | 500 mg tablets 1 or 2 tablets q4h, oral. Do not exceed more than eight tablets per day | B |
| Acetaminophen/aspirin/caffeine | Tablets contain 250 mg of aspirin, 65 mg of caffeine, and 250 mg of acetaminophen 1-2 tablets q3h, oral; do not exceed more than four tablets per day | A (caffeine dose ≤ 200 mg daily) |
| Sumatriptan | Intranasal: 10 mg-20 mg Oral: 25, 50, 100 mg Subcutaneous: 4, 6 mg Dose Intranasal: 40 mg/d Oral: 50 and 100 mg q2h; maximum 200 mg/d Subcutaneous: 4-6 mg q3h maximum dosing: twice daily |
C |
| Eletriptan | 20 and 30 mg tablets 40 mg q4h, oral |
C |
| Rizatriptan | 5 and 10 mg tablets 10 mg q4h, oral |
C |
| Almotriptan | 6.25 and 12.5 mg tablets 12.5 mg q4h, oral |
C |
| Frovatriptan | 2.5 mg tablets 2.5 mg q4h, oral |
C |
| Naratriptan | 1 and 2.5 mg tablets 1 tablet q3h, oral; maximum three doses per day |
C |
| Zolmitriptan | 2.5 or 5 mg tablets 5 mg, q3h, oral, as needed |
C |
| Dihydroergotamine | 1 mg intramuscular or intravenous 0.33 or 0.50ml on its first administration | X |
| Opioids | Oral or intramuscular These are limited per day and month | C |
| Metoclopramide | 5-10 mg tablets Migraine and nausea without vomiting: 10 mg/8 h, oral |
A |
| Ondansetron | 4-8 mg tablets 8 mg q3h, oral |
B |
| Dexamethasone | 4 mg q8h, oral, as needed. Maximum 8 mg/day | D |
| Prednisone | 20 mg q8h, oral, as needed. Maximum 40mg/day | C |
| Ergotamine | 0,5-1 mg, q6h -12h, oral | X |
| Lasmiditan | 50-100 mg, oral, per event | NA |
| Amitriptyline | 10-25 mg up to 400mg, oral every bedtime | C |
| Imipramine | 10-25 mg up to 400mg, oral every bedtime | D |
| Topiramate | Titrate over 4 weeks until effect. Week 1: 25 mg, oral every bedtime Week 2: 25 mg, oral q12h Week 3: 25 mg, oral in the morning and 50 mg oral every bedtime Week 4: 50 mg, oral q12h |
D |
| Sodium Valproate | 250 mg, oral q12h for 1 week May increase up to 1000 mg/day if needed | D |
| Propranolol | 80 mg/day, oral, divided q6-8h; may be increased by 20-40 mg/day every 3-4 weeks; not to exceed 160-240 mg/day split q6-8h | C |
| Flunarizine | 5-10 mg, oral every bedtime | NA |
| Onabotulinum toxin A | The recommended total dose is 155 units, as 0.1 mL (5
units) of intramuscular injections per site divided across seven
head/neck muscles q12 weeks. Frontalis: 20 units divided into four sites Corrugator: 10 units divided into two sites Procerus: 5 units in 1 site Occipitalis: 30 units divided into six sites Temporalis: 40 units divided into eight sites Trapezius: 30 units divided into six sites Cervical paraspinal muscle group: 20 units divided into four sites |
C |
| Erenumab | 70 mg, subcutaneous once monthly OR 140 mg subcutaneous once monthly (administered as two consecutive 70-mg subcutaneous doses) | NA |
| Galcanezumab | Loading dose: 240 mg subcutaneous once (i.e., two consecutive 120 mg subcutaneous injections) Maintenance dose: 120 mg subcutaneous monthly | NA |
| Fremanezumab | 225 mg subcutaneous once monthly OR 675 mg every 3 months, administered as three consecutive 225 mg subcutaneous doses | NA |
| Eptinezumab | 100 mg intravenous every 3 months OR 300 mg intravenous dose every 3 months | NA |
| Lidocaine nerve block | Every 2 or 4 weeks | B |
Table 2 Pregnancy risk category definitions
| A | Commonly acceptable. Controlled studies in pregnant women show no evidence of fetal risk. |
| B | It can be acceptable. Either animal or human studies demonstrated no harm, human studies are unavailable, or animal studies demonstrated minor risks. |
| C | Use with precaution only if the benefits outweigh the risks. Animal studies have demonstrated fetal risk, but human studies have not been available or demonstrated no risk. |
| D | Only use in cases where life is compromised. There is evidence of human fetal risk. The benefits may outweigh the risks. |
| X | Contraindicated, do not use in pregnancy. Use alternatives as risks outweigh benefits. |
NA: information not available
Conclusion
The treatment objective is to reduce the severity of headaches as possible, restore functioning ability, reduce the use of drugs, and promote management with minimal side effects. These goals are not different when treating pregnant women. Still, non-pharmacological treatment of migraine is preferable whenever possible, and preventive migraine drugs should be used only in severe and selected cases. After balancing risks and benefits, the lowest effective dose and frequency should be prescribed. Pregnant women should be counseled to avoid migraine triggers by having a regular sleeping schedule, avoiding missing meals, and practicing relaxation techniques such as mindfulness and yoga.
