Migraine has a higher prevalence in women, especially during reproductive years,1 presenting a clinical challenge of balancing the risks and benefits of migraine treatment against potential risks to fertility and offspring for women with childbearing potential. For those planning pregnancy, a preconception office visit can ease concerns about medication use for migraine treatment during pregnancy. During this visit, an individualized migraine treatment plan for use in pregnancy can be created, which can ease stress related to treatment.
Effect of Pregnancy on Migraine
Migraine headaches often improve during pregnancy, but have also been to known to worsen or start during pregnancy.2,3 A link between migraine and the female sex hormones, estrogen and progesterone, is seen in menstrual migraine and migraine in pregnancy.3 Almost half of women with migraine have improvment during the first trimester (46.8%), and this improvement increases substantially in the second (83%) and third (87.2%) trimesters.4 The number of women with complete remission in the first trimester is low (10.6%); however, the rate of complete remission increases significantly as pregnancy progresses (78.7% in third trimester).5 Migraine with aura is less likely to improve or remit compared with migraine without aura.5 In a study of pregnant women with menstrual migraine, participants reported increased headache intensity but not frequency early in pregnancy (week 7), compared with pregnant women whose migraines were not menstrual.6 Regardless of whether women’s migraines were menstrual or nonmenstrual, headache intensity decreased during the second half of pregnancy as did frequency of analgesic use.6
Migraine itself may be a potential teratogen. A retrospective study showed that women treated for acute migraine had higher rates of preterm delivery, preeclampsia, and low birthweight.7 A more recent prospective observational study, however, showed no teratogenic effect of migraine itself.8
Pregnancy Labeling Rules
Risk stratification of pharmacologic intervention is important, because 70% of pregnant women report taking at least 1 prescription medicine.9 In 2015, the Food and Drug Administration (FDA) implemented the Pregnancy and Lactation Labeling Rule, removing previously used letter codes for pregnancy risk stratification in exchange for a narrative summary. This summary includes any human, animal, and pharmacologic risk data available. The new system eliminates what some considered an overly simplistic pregnancy risk system that did not detail current data available on each pharmacologic agent. With the new labeling system, clinicians cannot rely on a predetermined risk category, but need to review the current data and make an informed decision on a case-by-case basis. The lack of a standardized risk assessment is both a strength and weakness of this update, requiring individual review of each medication for a specific individual.10
Preventive Treatment in Pregnancy
It is best to start nonpharmacologic behavioral changes known to decrease frequency and severity of migraines before pregnancy to make them learned behaviors. These approaches include relaxation therapy, biofeedback, and behavioral sleep modification, the latter of which may revert chronic migraines to episodic.11,12 Although these approaches are viable first-line treatment options for some pregnant women or individuals considering pregnancy, they may not be sufficient for others. For women with high frequency of migraine or significant disability due to migraine, the risk of pharmacologic agents needs to be weighed against the health consequences of untreated migraine, which can negatively affect both the mother and fetus. Untreated migraine can lead to poor oral intake, resulting in inadequate nutrition and dehydration in addition to sleep deprivation, increased stress, and depression.13
Vitamins and Minerals
Supplements and vitamins for migraine prevention may be an option for women who want an alternative to pharmacologic agents while pregnant. Intravenous magnesium, however, now has a warning against use in pregnancy because of concern that prolonged high doses of intravenous magnesium sulfate can cause fetal low calcium and bone abnormalities.14 Oral magnesium has not been associated with teratogenic effects and likely can be considered as a preventive option.15 Riboflavin and coenzyme Q10 (CoQ10) both have some efficacy in migraine prevention with limited studies in pregnancy; neither is known to be associated with adverse pregnancy outcomes. Riboflavin may be beneficial in reducing hematologic risks (eg, anemia during pregnancy), and CoQ10 may reduce risk of preeclampsia.16,17 Riboflavin and CoQ10 may be effective for migraine prevention in pregnancy.
Oral Pharmacologic Agents
A recent cohort study evaluating outcomes of children born to mothers who used beta blockers during pregnancy showed no increased congenital malformation risk.18 A prior cohort study, however, did show an association between beta blockers and fetal growth restriction, preterm birth, and perinatal mortality. The use of beta blockers for migraine prevention in pregnancy may warrant close monitoring of fetal growth.19
The anticonvulsants valproate and topiramate are not safe in pregnancy. Valproate is a known teratogen that can cause neural tube defects and neurodevelopmental disorders.20 Topiramate is associated with an increased risk of cleft palate.21 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) should be avoided in pregnancy because of increased risk of miscarriages, renal and pulmonary malformation, and oligohydramnios.22
Data are lacking regarding outcomes for children born to mothers who used tricyclic antidepressants (TCAs) or selective norepinephrine reuptake inhibitors (SNRIs) during pregnancy. A meta-analysis of studies on venlafaxine and duloxetine exposure during pregnancy found no increased risk of fetal malformations. An association between TCA use and fetal malformations has been reported but is not consistent across studies.23
The new calcitonin gene-related peptide (CGRP)-blocking monoclonal antibodies (MAbs) approved for migraine prevention were not tested during pregnancy. Although MAbs are known to cross the placenta, administration of supra-therapeutic doses did not result in adverse fetal outcomes in animal models.24-26 Expressed in omental arteries of pregnant women, CGRP plays a role in vasculature regulation,27 and there is concern for pre-eclampsia because systemic levels of CGRP were lower in individuals with pre-eclampsia compared with normotensive individuals.28 Whether this is cause or effect remains unknown; however, given the role of CGRP and pregnancy vasculature we would avoid use of these agents during pregnancy until further studies are performed. Providers should take into consideration that these medications have a month-long half-life. In our practice, we advise discontinuation at least 5 months before conception.
Animal studies raised concern for teratogenicity from onabotulinumtoxinA initially. These animal studies occurred at higher doses than those used for migraine prevention, however.29 It is thought that the 150 kDa onabotulinumtoxin is too large to cross the placenta; investigations of other agents have shown that molecules larger than 500 Da cross the placenta only incompletely.30,31 In case reports of pregnant women with systemic botulism, respiratory compromise occurred, but pregnancy outcomes were normal. A single woman with botulism developed ventilator-dependent paralysis, but her fetus continued having visible movements and was delivered without evidence of botulism.32 A retrospective review of 232 women with exposure to onabotulinumtoxinA 3 months before or during pregnancy did not show an increased prevalence of fetal abnormalities. Of the 137 cases with dose information, 45.2% were exposed to 100 units or more.33 In a report of a woman who received onabotulinumtoxinA for migraines while 18 weeks pregnant, complete resolution of migraines occurred, and her child was born without birth defects and had typical development during 6.5 years of follow up.34 We recommend practitioners considering use of onabotulinumtoxinA for preventive treatment of chronic migraine during pregnancy discuss the available literature and risk versus benefit with the patient and in consultation with colleagues in maternal-fetal medicine.
Abortive Treatment in Pregnancy
Acetaminophen is commonly used as an abortive agent for migraine and is considered safe during all trimesters of pregnancy. Acetominophen use is reported by 65% of pregnant women.35 There was some concern of an association between acetaminophen use during pregnancy and neurodevelopment effects, (eg, attention deficit hyperactivity disorder [ADHD]) in children with more than 28 days in utero exposure .36 The European Medicines Agency, however, found the data for this association insufficient.37
Non-steroidal anti-inflammatory drugs (NSAIDs), although commonly used for migraine treatment, have limited use in pregnancy. As prostaglandin synthetase inhibitors, NSAIDs can affect fetal development in a trimester-specific manner.38 Some studies have shown NSAID use in the first trimester leads to congenital malformations and miscarriages.38,39 A more recent study, however, evaluating the teratogenicity of NSAIDs in the first trimester did not find significant embryonic risk in women exposed to NSAIDs compared with women who were not exposed.40 In the third trimester, NSAID use should be avoided because of the known risk of premature ductus arteriosus closure and other adverse fetal outcomes.41
Metoclopramide is a preferred antiemetic during pregnancy with established safety in the treatment of hyperemesis gravidarum.42 The combination of parenteral diphenhydramine and metoclopramide is an effective migraine abortive when acetaminophen is not sufficient.43
Triptans are a mainstay abortive treatment for individuals with migraine. In a prospective observational study of triptan use in pregnancy, there was no increased risk of birth defects, spontaneous abortions, electively terminated pregnancies, or preterm delivery.8 In this study, the majority of the women were exposed to a triptan in the first trimester (75.2%). There was a higher rate of placental abruption in women exposed to triptans, but this was not statistically significant. Sumatriptan is the best studied and thus a preferred choice in pregnancy. Because there is not enough data on fetal outcomes after eletriptan or frovatriptan exposure to draw conclusions, fetal ultrasound is suggested for women exposed to these less well-studied triptans in the first trimester.8 Ergotamine derivatives are contraindicated in pregnancy because they precipitate uterine contraction resulting in increased risk of miscarriage and are associated with neural tube defects.44
Occipital and trigeminal peripheral nerve blocks (PNBs) (see Procedural Treatments for Headache Disorders in this issue) can be used in pregnancy for migraine treatment, and we frequently use them in our clinic. In a case series of women treated with PNB for status migrainosus or short-term migraine prophylaxis during pregnancy, most individuals had immediate post-24-hour pain relief, and there were no reported maternal or fetal adverse events attributable to PNB. There were 2 individuals who did not experience any relief of their headache with the nerve block; both were eventually found to have preeclampsia.45 Expert consensus recommends using lidocaine for nerve blocks in pregnancy and avoiding bupivacaine, which crosses the placenta.46 The addition of steroids do not have evidence for improved efficacy in migraine and have the added risk of accelerating fetal lung development.46,47
There are 3 neuromodulation devices with FDA approval for use in migraine (see Neuromodulation Therapies for Headache in this issue). Single-pulse transcranial magnetic stimulation and supraorbital nerve stimulation are approved for both preventive and abortive treatment and noninvasive vagal nerve stimulation is approved for abortive treatment. Although there are no specific evaluations of these devices in pregnant women, no fetal malformations or birth defects have been observed in animal studies, post-marketing surveillance, or open-label studies.48-50
It is prudent for providers to develop a plan for preconception counseling and migraine treatment during pregnancy. In our practice, the providers collaborated to develop a preferred stepwise plan for treatment of migraine from conception trials through each trimester of pregnancy. This plan weighs the efficacy and urgency of treatment for migraine with possible adverse fetal effects. Any conception plans are addressed during the new patient visit and counseling is given to make a specific follow-up at least 6 months before trying to conceive.
During the preconception visit, plans to discontinue preventive medication prior to conception are discussed and a risk/benefit analysis is reviewed. Discontinuation of preventive treatments may significantly increase migraine-related disability, so individuals are encouraged to work closely with their obstetrician to proactively address fertility concerns and counseled to optimize lifestyle modifications including cardiovascular exercise and sleep hygiene. Nonmedication interventions including prenatal yoga, biofeedback, and acupuncture are discussed. During the prenatal counseling visit, acute treatment options during conception trials and pregnancy are discussed. For women who use an ovulation tracker, we encourage use of standard migraine treatment for acute attacks from menses until ovulation. After ovulation, first-line treatment is acetaminophen, which is continued if pregnancy occurs. In addition to acetaminophen, our preferred abortive regimen includes caffeine, diphenhydramine and/or metoclopramide, followed next by sumatriptan. Neuromodulation devices are often discussed prior to conception and a trial is recommended then to see if it would be an effective treatment option. All treatment decisions are made in conjunction with a discussion of the available data for use of each medication in pregnancy.
If preventive medication needs to be started during pregnancy, severity of disease is weighed against trimester of pregnancy. In the first trimester, lidocaine nerve block every 2 to 4 weeks is the preferred treatment. Second-line preventive options include propranolol or amitriptyline and are often initiated in collaboration with maternal-fetal medicine. For individuals with chronic migraine who had therapeutic improvement with onabotulinumtoxinA but do not respond to nerve blocks, on a case by case basis and in consultation with maternal fetal medicine, we will restart toxin. This is often preferred to treatment with an oral preventives tried before pregnancy without benefit or with intolerable side effects.
Migraine is common in women of childbearing age. Standard treatments for migraine may carry risk to the developing fetus. In order to optimize treatment of migraine during pregnancy, preconception visits should be encouraged prior to conception trials. These visits can ease the stress of conception for women with migraine and can review important information about safe treatment options.
CD has received speaking honorarium from Amgen, electroCore, Eli Lilly, and Teva; consulting fees from Alder, Biohaven, Clearview Health Partners, Guidepoint Consulting, PQA, and Promius Pharma; and compensation for contributions to MedLink Neurology. JA has received speaking honoraria from Allergan, Amgen, Eli-Lilly, Promius Pharma, electroCore, and Teva; consulting fees from Alder, Allergan, Amgen, Biohaven, Eli Lilly, Promius Pharma, electroCore, Teva, Impel, Satsuma, Aptus, Alpha Sites, Miller Medical Communications, and Forefront; editorial honoraria from Current Pain and Headache Reports as section editor for Unusual Headache Syndromes; and research funding from American Migraine Foundation for the ARMR registry. CO has nothing to report.
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