A pregnant special ed teacher is having horrible, pounding headaches with light and sound sensitivity, nausea and vomiting, and her doctors have recommended... Tylenol? In this episode, we review migraine physiology, and pharmacological and behavioral treatment of this debilitating neurological disorder in pregnancy. Experts include neuroscientist Dr. Carl Saab, obstetrical medicine specialists Drs. Niharika Mehta and Kenneth Chen, and behavioral medicine specialist Dr. Lucy Rathier. Dr. Julie Roth hosts.
Migraine is a complex neurological syndrome that can be affected by a number of triggers - including sex hormones! This means there are many women whose migraines increase during pregnancy.
Treatment of migraine in pregnancy can be tricky, because the list of SAFE medications in pregnancy does not necessarily match the list of EFFECTIVE medications.
The Pregnancy and Lactation Labeling Rule (PLLR) offers more information about safety of drugs in pregnancy than the old FDA "letter category" classification system. Clinicians can use this as a framework to discuss medications and their risk profile in pregnancy individually with pregnant or lactating patients with migraine.
- In addition to medicines, there are a number of effective behavioral therapies that can treat migraine, which would be considered safe in pregnancy.
Written Case: Migraine in Pregnancy
Dr. Julie Roth and Dr. Niharika Mehta
A 36 year-old G2P1 pregnant woman, currently at 8 weeks gestation presents for evaluation of headaches. Her headaches are characterized by throbbing or pounding pain at one or both temples, with light sensitivity and nausea. She has a prior history of migraine since age 16, which have always been strongly hormonal. Her physical exam is normal, including funduscopic exam. Her prior pregnancy was notable for severe headaches in her first and early second trimester, characterized by a gradual buildup of throbbing pain in the forehead and around the eyes, lasting hours to all day, often on one side, with light and sound sensitivity, and rarely, with nausea.
What clues do you have regarding diagnosis and treatment? What is the most likely diagnosis for this patient’s headaches?
In a pregnant patient, a longstanding history of headaches from an early age and a normal exam (including funduscopic exam), are reassuring factors that confirm the current diagnosis of migraine in pregnancy. In this case, the patient has a history of prior pregnancy during which headaches were also a feature. It is important to consider clinical features of current prior headaches, a list of medications and treatment strategies that worked and did not work, and the patient’s understanding of headaches and medication use in pregnancy.
Workup for new onset headaches (or atypical headaches) in pregnancy will be covered in another case. In this particular patient, no further testing is indicated, as she meets criteria for episodic migraine headache. Throbbing headaches of gradual onset, lasting hours, and accompanied by sensory hypersensitivities such as photophobia and phonophobia, as well as nausea, are characteristic of migraine headaches. The International Headache Society defines migraine without aura as at least five attacks (not otherwise explained by another neurological disorder), lasting 4-72 hours untreated, with at least two of the following characteristics: unilateral location, pulsating quality, moderate or severe intensity, aggravation with physical activity or exertion, and at least one of the following characteristics: nausea (with or without vomiting) or sensitivity to light or sound.
What is a migraine? And why does it occur?
Migraine pathophysiology is complicated. The primary mechanisms appear to be neuronal dysfunction with associated changes in bloodflow, and activation of the trigeminovascular system, triggering release of calcitonin gene-related peptide (CGRP), among other neuropeptides. The aura of migraine is caused by an electrical phenomenon known as cortical spreading depression of Leao (CSD) – characterized by progressive hyperpolarization of adjacent neurons throughout the cortex of the brain. Hypersensitivity of sensory neurons and the central nervous system are key elements in the perception of mild stimuli like light and sound as painful to a patient during a migraine attack.
How common is migraine, and whom does it affect?
Migraine is more common in women than men (3:1) and in most cases appears to have genetic underpinnings; about 70% of migraineurs have a first degree relative with migraine. Migraine attacks are often triggered by factors that are common in pregnancy: changes in sleep, stress level, hormones, caffeine intake, and diet.2 While many women find a hormonal trigger to their migraines, in clinical practice, it can be hard to predict whether a woman’s migraines will improve or worsen in pregnancy. On the other hand, for women with hormonally triggered migraines, weaning from breastfeeding can exacerbate migraine attacks.
Migraine occurs in 11-26% of women of childbearing age, and although the prevalence of migraine specifically during pregnancy is unknown, up to one third of pregnancies are complicated by headache. While not immediately life-threatening, migraines can be disabling and contribute to poor absorption and even dehydration through gastrointestinal effects. Migraines – and in particular, migraine with aura – are considered minor risk factors for stroke and cerebrovascular diseases. There are links between migraine and hypertensive disorders of pregnancy. Furthermore, severe pain – including migraine – can be associated with stress, dehydration, and other factors that may adversely affect a pregnancy. Therefore, a diagnosis of migraine in pregnancy should be addressed from a medical standpoint. Several studies indicate a significant association between migraines and hypertensive disorders of pregnancy (PEC and Gestational HTN) . In addition, migraines are a risk factor for stroke in pregnancy and puerperium.
During her prior pregnancy, she took amitriptyline up to a dose of 50mg/day, for migraine prevention. This helped somewhat. She has had several headaches so far that were severe (9 or 10/10 pain), and did not respond to acetaminophen. She wonders if she can take the sumatriptan she typically takes outside of pregnancy.
What medications can be used safely in pregnancy for acute treatment of headache? What daily preventative medications are safest? Which of these medications are most effective?
The FDA “category” system classifies medications based on levels of potential risk in pregnancy. Category A medications have demonstrated on risk in controlled, human studies (based on exposure in all three trimesters). Category B medications have demonstrated no risk in other studies, including animal studies – in other words, there has been no proof of risk in humans. Category C medications may have demonstrated some adverse effects in animal studies, but no well-controlled human data to make a recommendation. It is noteworthy that 2/3 of all medications fall in the “C” category. For category C medications, risks and benefits must be carefully weighed. For category D medications, there has been evidence of human risk, and category X medications are contraindicated in pregnancy due to high fetal risk.
The medications considered most effective for acute treatment of migraine outside of pregnancy include: triptans, such as sumatriptan: nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, and ergotamines, which are less frequently used due to side effect profile. Of these, sumatriptan is considered category C in pregnancy, and so the risks and benefits must be discussed with patients on an individual level. Specifically, sumatriptan can raise blood pressure – which can be risky later in the third trimester. Full dose aspirin is in fact contraindicated throughout pregnancy. However, other NSAIDs such as ibuprofen are contraindicated after 20 weeks due to the potential for closure of the patent ductus arteriosus. Before 20 weeks gestation, NSAIDs can be used sparingly. Acetaminophen is a mild medication and is less commonly used for migraine outside of pregnancy; however, it is considered the safest analgesic to use in pregnancy (category B), and it can be effective if used early in a migraine, especially in conjunction with caffeine and metoclopramide, an antiemetic. Opioids are not typically used for migraine outside of pregnancy given the risks of addiction and analgesic rebound headaches; however, they are considered safe to the fetus if other methods of treatment fail.
A frequency of at least one headache per week in a nonpregnant patient usually suggests the need for a daily preventative medication. Medications used for the preventative treatment of migraine outside of pregnancy were reviewed in a 2012 AAN/American Headache Society guideline. Those medications that received the highest level of evidence for efficacy (Level A or B evidence) included valproic acid and topiramate – both of which are anticonvulsants considered category D in pregnancy. For women who become pregnant while taking either of these drugs for migraine prevention, neurologists usually recommend stopping the medication in favor of a safer option. Metoprolol and propranolol received level A evidence for efficacy against migraine; both are category C in pregnancy. Amitriptyline is also category C in pregnancy and received level B evidence of efficacy against migraine. While there are a number of other options, these three drugs are among the most popularly prescribed to pregnant women for migraine prevention, because of their favorable risk/benefit ratio. It is also worth mentioning that magnesium oxide in doses up to 400mg per day is often considered first line in pregnancy as a migraine preventative (level B evidence of efficacy) and is thought to be safe. There has been recent controversy about magnesium sulfate injections – usually used for treatment of preeclampsia/eclampsia – given the potential effects of long-term use (more than 5-7 days in a row) of these injections on fetal bone health, leading to a category D designation from A. However, these are two different formulations and doses of this supplement.
In 2015, the FDA changed the labeling requirements of medications in pregnancy and lactation – known as the Pregnancy and Lactation Labeling Rule, or PLLR. Each drug that is now FDA-approved will have a PLLR data sheet included, instead of a category designation. These data sheets list all animal and human studies detailing risk in pregnancy and lactation; drugs developed between 2001 and 2015 will retrospectively be given PLLR designations, a process that will be rolled out gradually. The PLLR labeling requirements are thought by many clinicians to be a more informative approach to safety in pregnancy and lactation. Other resources regarding the safety of drugs in pregnancy include TERIS and REPROTOX.
What non-medication strategies can be used to treat migraine in pregnancy?
Nonpharmacological methods of migraine prevention include nerve blocks – occipital nerve block, for example – and complementary therapies such as physical therapy, acupuncture, and behavioral treatments. Many pregnant women prefer not to take medications in pregnancy at all, and for them, these therapies – especially behavioral therapies – are ideal. One aspect of behavioral therapy is the identification of triggers. The major migraine triggers include stress, hormones, diet (missed meals more than specific food triggers), weather, sleep changes, odors, neck pain, lighting/glare, neck pain, exercise/exertion, caffeine intake and dehydration. Many of these triggers can be magnified in pregnancy. The other major aspects of behavioral therapy include relaxation strategies, biofeedback, and cognitive behavioral therapy – a restructuring of thought processes to avoid a maladaptive emotional response to migraine. These strategies – in particular, cognitive behavioral therapy and thermal biofeedback (often in conjunction with autogenic relaxation), have high level evidence for efficacy against migraine, and can reduce migraines by 30-60%. These strategies are appealing to pregnant women as an alternative to medications.
Are there labor and delivery considerations for migraines in pregnancy? In the postpartum period?
There are no special labor and delivery considerations in this population. The labor and delivery process should not put women at particular risk for migraine. However, after weaning from breastfeeding, hormonally mediated migraines can worsen in women, and appropriate steps must be taken. As a general rule, medications that are deemed safe in pregnancy can also be used in lactation.
 International Headache Society, Diagnostic Criteria for Migraine Without Aura. 2016. https://www.ichd-3.org/1-migraine/1-1-migraine-without-aura/
 Roth JL and Bilodeau C, “Headaches and Seizures.” Rosene-Montella K, Medical Management of the Pregnant Patient. New York: Springer 2015. (219-231)
 Bushnell CD et al. Migraines during pregnancy linked to stroke and vascular diseases: US population based case-control study. BMJ. 2009;338:b664.
 Pearce CF, Hansen WF. Headache and neurological disease in pregnancy. Clin Obstet Gynecol. 2012;55:810-28.
 Loder E, Burch R, Rizzoli P. The 2012 AHS/AAN Guideline for Prevention of Episodic Migraine: A Summary and Comparison With Other Recent Clinical Practice Guidelines. Headache 2012;52:930-945.
 Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78:1337-1345.
 Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1346-1353. doi:10.1212/WNL.0b013e3182535d0c. (RETIRED: due to concerns about safety concerns in recommendation for butterbur.)
 Tepper D. Headache Toolbox: Magnesium. https://americanheadachesociety.org/wp-content/uploads/2016/06/Magnesium.pdf
 Magnesium sulfate use in obstetrics. Committee Opinion No. 652. American College of Obstetricians and Gynecologists. Obstet Gynecol 2016;127:e52-3.
 Kelman L. The triggers or precipitants of the acute migraine attack. Cephalalgia 2007 May;27(5):394-402. Epub 2007 Mar 30.
 Rathier L and Roth J. A Biobehavioral Approach to Headache Management. Rhode Island Medical Journal, February 2015;26-28.