Migraine symptoms improve in up to 70% of women during pregnancy, usually during the second and third trimesters. But in 4%–8% of women, migraines worsen, and as many as 16% of all migraine cases during pregnancy may be new onset.
A 2002 review identified drugs or drug classes used for preventing migraine attacks (N. Engl. J. Med. 2002;346:257–70), including four drugs available in the United States that were considered well-accepted treatments or had proved to be effective: metoprolol, propranolol, amitriptyline, and valproate. Verapamil (Calan, Isoptin) and selective serotonin-reuptake inhibitors (SSRIs) also were widely used, but the reviewers concluded that there was poor evidence of benefit. Gabapentin (Neurontin) and topiramate (Topamax), were considered promising for migraine prophylaxis.
Only amitriptyline, verapamil, and low-dose propranolol (30–40 mg/day) have sufficient data to be classified as low risk throughout pregnancy. But higher doses of propranolol may cause intrauterine growth retardation (IUGR) and other fetal/neonatal toxicity. Based on the drug class (antihistamine and calcium channel blocker), flunarizine is probably compatible with pregnancy. Gabapentin and topiramate should be avoided in the first trimester because of inadequate human data to assess their risk. Valproate is known to cause neural tube defects and other structural anomalies if used in the first trimester, and use of metoprolol during the second and third trimesters is associated with an increased risk of IUGR. Use of the SSRIs in the third trimester may cause newborn toxicity, and methysergide and other ergot alkaloids are contraindicated in pregnancy.
Many other drugs have been used in treating migraines, including: acetaminophen (alone, or in combination with caffeine and butalbital, aspirin and caffeine, or isometheptene and dichloralphenazone); NSAIDs, including aspirin; chlorpromazine (Thorazine); dimenhydrinate (Dramamine); diphenhydramine (Benadryl); morphine; meperidine; intranasal butorphanol (Stadol); and corticosteroids.
Combination products with butalbital are not recommended because in studies, the butalbital component did not increase efficacy. Acetaminophen, caffeine, dimenhydrinate, diphenhydramine, narcotic analgesics, lidocaine, and butorphanol are compatible (i.e., very low risk) in pregnancy. However, frequent, prolonged use of narcotic analgesics may result in maternal and fetal addiction.
NSAIDs, including aspirin, have been associated with miscarriage when used around the time of conception, and exposure in the third trimester is associated with premature closure of the ductus arteriosus with the risk of persistent pulmonary hypertension of the newborn.
Since aspirin causes irreversible inhibition of platelet function and other clotting disorders, its use near term may enhance maternal blood loss at delivery and increase the incidence of intracranial hemorrhage in premature infants. Use of corticosteroids in the first trimester is associated with a low risk of oral clefts. Ergot alkaloid preparations are contraindicated in pregnancy because of dose-related developmental toxicity and oxytocic properties.
In the United States, seven triptans indicated for the short-term treatment of migraine with or without aura are available: sumatriptan (Imitrex), almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), and zolmitriptan (Zomig). Triptans do not appear to be major teratogens in humans, but more data are needed to adequately assess this risk.
In animal studies at doses or systemic exposures 10 times the human dose, triptans caused developmental toxicity. Human data, primarily from pregnancy registries, are available only for naratriptan, sumatriptan, and rizatriptan. As of early 2004, about 500 women had been prospectively enrolled, about 90% with first-trimester exposure. Except for a small cluster of five ventricular septal defects, a common heart condition, there was no consistent pattern of defects to suggest a common cause.
Other than ergot drugs (contraindicated) and amitriptyline (concern for long-term neurotoxicity), all antimigraine agents appear to be compatible with breast-feeding. However, there are few or no data available for gabapentin and topiramate. Ergot alkaloids may inhibit lactation, and high doses have been associated with toxicity in nursing infants. The effect of triptans on a nursing infant is unknown, but the small amount of drug found in milk does not appear to represent a risk and it is probable that they are all compatible with breast-feeding.