Guest: Andrea Murphy, MSN, APRN, ANP-BC, NEA-BC, AQH

View the recording from our Migraine Clinician Masterclass, developed in partnership with IVPN Neuropsychiatry. In this webinar, we hear from Andrea Murphy, MSN, APRN, ANP-BC, NEA-BC, AQH, who talks about Managing Migraine During Pregnancy. Please note that this video is intended for healthcare providers.

TRANSCRIPT

Andrea Murphy, MSN, APRN, ANP-BC, NEA-BC, AQH: So my presentation is on The Treatment of Migraine During Pregnancy and Breastfeeding: What are the Options and Challenges? 

Here are my disclosures. 

And today we will be talking specifically about the impact of migraine on this population of women during pregnancy and breastfeeding. I also would want to make sure we discuss there may be some secondary headaches to consider when a woman comes with an atypical presentation of headache while pregnant or breastfeeding. And then probably most of interest is what are the treatment options that are available? 

So first talking about more of the epidemiology, we know pregnancy is common. We don’t have to share that with you today. However, migraine is equally common. So worldwide, migraine is the second leading cause of years lived with disability. And it’s disproportionate where it affects men less so compared to women. So after adolescence, women are impacted more. And about one in five women will experience migraine. 

Also, the most common age for women to be impacted by migraine are during their reproductive years. So between the ages of 15 to 44 years old, which is also the demographic we’re talking about today. And not a surprise, a majority of women, up to 80% of women with migraine will experience migraine during pregnancy. 

I have listed here the criteria for diagnosing migraine. And this comes from the International Classification of Headache Disorders. And so migraine is a diagnosis, a headache of a longer duration headache. So at least 4 hours; however, can go on if untreated or unsuccessfully treated for days, even greater than 72 hours. 

And so this headache, at least two of the following four characteristics. So it can be unilateral, pulsating in quality, tends to be debilitating, so moderate or severe pain intensity, aggravated by or causing avoidance of routine physical activity. So returning, really impacting a woman’s quality of life. 

And D listed here, during headache, at least one of the following. So someone with headache may also report nausea and/or vomiting or sensitivity to light or sound, photophobia and phonophobia. So this is migraine without aura, which is more common. 

However, someone may also have migraine with aura. In the literature, about 20 to 25% of migraine sufferers may also have migraine with aura. So it fulfills similar category with migraine. However, they may also experience one or more of the following reversible, emphasis being on reversible, aura symptoms. Most common is vision, scotomas, funny spots, things like that, can last anywhere from five to 60 minutes. 

Sensory or speech language can also occur. Two or more symptoms can also happen at the same time. And at least one aura symptom is one-sided, typically can be on the side where someone is experiencing the headache. And again, I like to emphasize this is fully reversible and typically lasts less than an hour. 

Hormonal changes that affect women with migraine are common. It’s not surprising to hear a woman may describe even their first migraine started at the start of when their periods began. And in fact, menstrual migraine, we know even if a woman is having migraines at other times of the month during menstruation, those headaches can be more debilitating. Oftentimes those are when they’re missing time from work or school or important life events.

Here you can see listed on my slide, there are other hormonal milestones. Particularly we’re going to talk about pregnancy and breastfeeding, but even any type of birth control can either be a triggering factor or particularly those that are triphasic in nature, or some oral contraceptives can actually be used as a treatment for menstrual migraine. Particularly those that are monotherapy are more likely to help keep hormones and homeostasis in balance. Then there’s also perimenopause, menopause, and the use of hormonal therapies.

So particularly hormonal changes during pregnancy, what is happening usually when a woman becomes pregnant, estrogen levels are rising, and then there’s lack of estrogen cycling or ovulation. And so when that happens, generally women feel better. So two-thirds of women experience improvement, particularly in the second and third trimester, because that’s when estrogen has risen much higher.

However, some women do not, the point of our talk today. And unfortunately, women who describe migraine with aura are less likely to improve their migraines during pregnancy. There have even been reports of migraine or migraine with aura being the first time during pregnancy. Again, that hormonal milestone. 

What about postpartum? So we talked a little bit about pregnancy, what’s happening hormonally. So the opposite happens postpartum. So a woman say if they felt better during pregnancy, particularly as their pregnancy progressed, about one out of two women, 50%, report their migraines soon return postpartum, even within a few days of delivering their baby. And what’s happening in the body is estrogen levels are falling. And there’s also changes in the endothelial lining.

Not to mention more commonly reported migraine triggers are also present. For example, environmental factors, right? So the stress of having a new baby, lack of sleep, dehydration, these triggers can compound migraine postpartum. I listed here, there’s a statistic where about a third of women will have migraine recurrence the first week and 50% within the first month.

However, there can be some hormonal reasons why breastfeeding can be protective, particularly related to oxytocin release, maybe an area of opportunity still for the future. And then I wanted to make note that there can be secondary headaches if you’re a practitioner listening on this call to be aware of. So anyone who was having more atypical headaches really want to consider things like RCVS, which is reversible cerebral vasoconstriction syndrome or cerebrovenous thrombosis, even preeclampsia, especially within those first couple months postpartum. These would be headaches with increased morbidity and mortality. 

So most women who are pregnant and have migraine, there doesn’t need to be any further evaluation. However, this mnemonic here is to screen for any red flags and pregnancy is on the list. So if someone, I like to give examples of a new or unexplained abnormal finding on their neurological exam, atypical headache features, headaches that don’t fulfill migraine criteria that we just went over through the ICHD, sudden severe headache, worst headache of your life, significant changes in the characteristics, or they’re having other symptoms. Examples might be fever, stiff neck, elevated eye pressure. This would be a reason to further evaluate and make sure we have the correct diagnosis at hand, particularly ruling out more worrisome secondary causes for headache. 

So this is a single-center, retrospective review. It’s a few years old now by some of my colleagues in New York, but the take-home is secondary headaches do happen during pregnancy. About a third of pregnant women who came in for headache at their center did have a secondary headache. And here’s some of the examples. So vascular etiologies may be things like preeclampsia, eclampsia, venous thrombosis, stroke, any type of bleed or hemorrhage, PRES, RCVS, as well as arterial dissection.

And then there’s some non-vascular causes for secondary headaches listed like here, pituitary apoplexy, intracranial hypertension, also known as pseudotumor, and then tumor-including microadenoma. About 30% of women came in with secondary headaches. 

So I like to repeat, most women who are pregnant do not need a headache evaluation further if, you know, this is their typical migraine pattern. However, if there were any red flags we talked about, an MRI of the brain tends to be the gold standard. It’s preferred imaging study during pregnancy. And that’s because even though the risk of radiation is low, there is still radiation with a CT of the head. Gadolinium during an MRI should not be administered just because we know that actually causes fetal toxicity. But with any imaging study, we really want to mitigate the risk versus benefit to the mother and the fetus when deciding which scan to order. 

Challenges to treatment. So ideal scenario is preconception counseling when possible. Certainly, you know, having that dialogue, that open dialogue, even months, even years with your patient before maybe family planning is being considered. But ideal versus reality, right? So we know up to 50% of pregnancies are unplanned. So that doesn’t necessarily always happen. 

Also, the medication management during pregnancy and breastfeeding is understudied. Just because it’s understudied doesn’t mean that we don’t treat migraines. So particularly, what are the concerns about known treatments? So safety and teratogenicity of medications. Some we do know about and some are unknown, particularly looking more at long-term fetal neurobehavioral outcomes. 

And then almost on pregnant women, will you ever see a double-blind randomized controlled trial? That’s the gold standard, but that’s not reality in this population. And then more commonly, what is reality is seeing safety data that comes from retrospective case studies, particularly also registry studies or any type of bigger database studies, which we will review some of those today. 

What are the adverse effects if we don’t treat migraines during pregnancy? So here’s a couple statistics for you, but we know migraine attacks, especially those associated with vomiting, can lead to dehydration and electrolyte imbalances, requiring hospitalization during pregnancy. There is also, having a diagnosis of migraine, there is an increased risk, anywhere from 1.5 to threefold increased risk of developing preeclampsia, as well as other hypertensive disorders in pregnancy.

In terms of neonatal outcomes, there has been reported lower birth weight, also preterm birth as well, and longer NICU stays in babies, particularly concerns with respiratory distress syndrome and febrile seizures. 

Also, treatment of migraine during this population may reduce migraine-related presenteeism and absenteeism, particularly important also if you’re considering pregnancy-related discrimination in the workforce. Poor management has also been associated with physical and mental health conditions, both ante- and postpartum. These are all the reasons to treat migraine during pregnancy. 

So, the management of migraine during pregnancy in one slide. So, looking first at the top left, our lifestyle considerations. So, really optimizing their routine. So, looking at sleep patterns, hydration, diet, exercise, how are we coping with stress, incorporating behavioral treatments, and here’s a few, there are more. Things like biofeedback or cognitive behavioral therapy, which usually can be done by either a social worker or a psychologist in this field. Meditation, relaxation practices. 

And so, as you can see, most of these are non-medicinal lifestyle considerations, but so important to have discussions about with your patient, and not even, if possible, the ideal scenario when we’re talking about preconception counseling months in advance of family planning. 

Listed here is addressing risk factors for chronification. So, we know that there can be a progression of migraine as a neurological disorder, and the more common risk factors are sleep disturbances, such as insomnia, comorbid mental health conditions like anxiety, depression, previous trauma, obesity. So, looking at these risk factors more from a holistic perspective and really prioritizing the patient at hand can be very, very helpful. 

Then we move to the top right of this screen. So, other non-pharmacological treatments that can be helpful. Acupuncture, but particularly by a provider who is accustomed and familiar with treating pregnant women. Other physical treatments that are gentle are things like craniosacral therapy, osteopathic manipulation, massage, and there are some devices we will talk about in the slides to come.

The bottom of my slide here is talking more specific about prescription treatments, whether over-the-counter or prescription. So, abortives. So, these would be medications you would take as needed for a headache. First line is acetaminophen. It’s been that way for a long time, but we’re going to go beyond that during this talk and talk about other medications, particularly antiemetics can be helpful, like metoclopramide. Also, antihistamines like diphenhydramine and lidocaine we’ll talk a little bit more about.

Second-line treatments. Triptans are more migraine-specific, and then there’s some other antiemetics listed as well, promethazine, prochlorperazine, and some steroids listed here. 

Prevention. So, prevention means a medication typically that you would take every day to help with the overall frequency and debility associated with a woman’s headaches. It depends on the criteria you’re using, but typically it’s based on frequency. So, if someone is having greater than four headache days per month.

However, the conversation I have is really about their quality of life, and there’s different scores that can be used. Most common in my practice, we use the MIDAS score, which is a disability score. But at the end of the day, if somebody is missing work, really having a tough time during their pregnancy, you really would like to be considering preventive strategies in addition to making sure we’re focusing on the top of the screen, which is the lifestyle and non-pharmacological treatments.  First line is propranolol. We’ll talk a little bit more about magnesium as well and amitriptyline. 

So, before talking about medications, here’s a caution. So, I really want to stay from any medications that we already know is teratogenic, particularly any that can impact the uterus or cause vasoconstriction. Example in the migraine world, things like ergotamine. So, that would be things like dihydroergotamine or DHE. 

NSAIDs are, there’s a lot of information out there about data about NSAIDs, and really, it comes down to the gestational age. So, first trimester, I would avoid NSAIDs, any non-steroidal anti-inflammatory drugs. Particularly, there’s a concern for malformations as well as miscarriage. And then, after 30 weeks gestation, so we’re talking more in the third trimester, I would also avoid NSAIDs. Particularly, the concern is exposure to NSAIDs after 30 weeks, increased risk of premature closure of the fetal ductus arteriosus. There have also been concerns about lower amniotic fluid at that time impacting birth outcomes. 

Other caution is in any drugs of abuse, particularly opioids. Opioids is not ideal for the management of headache in general. Particularly, we know that opioids increase the risk of medication overuse and just complicate treating migraine. Benzodiazepines equally are not very effective treatments for migraine.

And what, at least here in the States, butalbital-containing products are actually fairly common, especially, you know, comfort level for women’s health providers. My team and I were involved with studying how OB/GYNs or women’s health providers feel in terms of their comfort level with treating migraine during pregnancy, and this medication is often used. However, there is some concern. So, particularly, there’s congenital heart defects, there could also be withdrawal from this medication postpartum, both for the fetus and the mother as well. 

And then, there’s the unknown, where we don’t know the risks of certain medications, some of the newer medications, for example, although we’re starting to learn as data comes available. 

So, looking at acute medications. So, these are medications you would use as needed for migraine. They are most effective if used early into a migraine attack, particularly within those first 30 to 60 minutes of migraine, which really should be enforced during the counseling. Triptans are migraine-specific treatments. So, they’ve actually been around for quite some time, you know, over 20 years now. 

Sumatriptan is probably the triptan we have the most information about in terms of safety data with pregnancy, but there are a total of seven triptans listed here. Imitrex is sumatriptan, Maxalt rizatriptan, Relpax is eletriptan, Zomig is zolmitriptan, Axert is almotriptan, Amerge is naratriptan, and there’s also Frova or frovatriptan.

So, these are migraine-specific treatments. They particularly work on 5-HT1B/D agonists on serotonin receptors. Particularly the way they work on migraine is they’re inhibiting the release of inflammatory peptides, also constricting vessels dilated by CGRP, which is exciting. A lot of newer medications also work on CGRP.

I like to enforce, because of the vasoconstriction, this would really be contraindicated treatments for anyone who has a preexisting cardiac history, particularly ischemic disease we’re talking about, or any poorly controlled hypertension, whether pre- or during pregnancy, coronary vasospasm. 

There are also many different formulations that triptans come in. Listed here, you’ll see tablets versus dissolvable, nasal sprays, sub-QTU injections, so it depends on patient preference, but also their migraine profile, if we need a medication to work faster or not.

Here’s some information about triptans and their safety. We actually do have a fair amount of larger studies. So, in 2015, there was a meta-analysis that looked over 4,000 infants who were, their mothers were using triptans in utero. So, there actually was no increase in major congenital malformations, premature birth, or spontaneous abortions among triptan users compared to women who weren’t on triptans. 

Another study I’d like to include here looked at 432 women, again, using triptans, and really there was no adverse outcomes mentioned. 

And then, what about long-term? We’re always concerned about behavior, the neurobehavioral outcomes. So, there is a Norwegian study, a cohort study, looking over five years’ time after in utero exposure to triptans. It looks like in utero, they scored, for some reason, they were higher in terms of sociability. We don’t really know what that means, but there was no negative developmental concerns long-term, at least within the five-year time frame.

So, in my own personal practice, I tell patients, you know, who have migraine, you know, there’s different levels, but if possible, we know that during organogenesis is most critical, during the first trimester, if possible to try to use medications very sparingly. But if needed, I tend to prescribe sumatriptan. We have the most evidence in terms of safety with sumatriptan.

This is not done alone. I am very fortunate to have a multimodal team where I work very closely with their OB/GYN. Also, I have some maternal-fetal medicine specialists who go at quite detail of all of the known literature that is available with medications used to treat migraine.

Typically, with breastfeeding, I tend to use eletriptan or Relpax only because of the pharmacokinetics. We know that eletriptan is highly protein-bound, so the likelihood of it being in breast milk is very, very low. 

All right, so now talking about preventives. So, these would be medications used for reducing the overall frequency and intensity of headaches and reducing headache-associated disability. The reason propranolol, also metoprolol, are considered first line is because we have the most data available. There is still some concerns for fetal growth restrictions with this medication, but most of the safety data actually comes from the women’s health field, particularly using beta-blockers during the treatment of preeclampsia. So, that’s preferred.

Second line, when we look at the tricyclic antidepressants, that’s amitriptyline or nortriptyline listed on this list. There’s also a fair amount, lots of study data on these medications. I do like to point out there is a risk of neonatal abstinence syndrome, so something for the OB team to be aware of that, you know, if you decide from a risk versus benefit standpoint, a mother stays on this medication.

Vitamins. So, CoQ10, typically the dosing is 300 mg daily. Magnesium is listed on third line. However, I use it very frequently. The dosing is anywhere, at least PO, from 400 to 600 mg of magnesium, and then also vitamin B2 is listed here, which is riboflavin. That’s 400 mg a day typically dosed. And so, I feel very comfortable offering vitamins to my patients. 

I will say, so magnesium, there have been reports, particularly in high-dose IV, concerns with magnesium competing with calcium and concerns for fetal bone development. So, that would be something just caution, but that’s not typically how it’s being used for migraine prevention. And that data actually came from the treatment of preeclampsia.

In terms of some other medications on this slide, so gabapentin and pregabalin, low risk of malformations. There are some reports of higher risk of preterm labor, low birth weight, although there are limited randomized controlled trials with these medications. 

All right, and then venlafaxine is listed here as third line. Inconsistent results across studies. There is some concern for increased risk of preterm birth. And this would be the case whether a woman was pregnant or not, there is an increased risk of hypertension, so it would need to be something to be monitored if chosen during pregnancy.

Medications, avoid when possible. Some of these medications, so the CGRP monoclonal antibodies we’re going to talk a little bit more about, but the ideal would be to stop four to five half-lives before conception, and that’s because they have a very long half-life, especially with the injectable treatment. The concern may be there may be an increased risk of preeclampsia. Again, none of this has been proven, but CGRP, we know, is a potent vasodilator, and so that may be necessary to support a woman during pregnancy. 

And then lisinopril is listed to avoid. Topiramate, the concern, while it’s still low, is there is a risk of cleft palate and lip within the first trimester, so generally I would avoid. And then feverfew can actually induce contractions, so concern for miscarriage. And we know valproic acid as well as methergine is teratogenic during pregnancy, so avoid altogether. 

What about procedures? So in general, most of these procedures can be done even in a primary care internal medicine office, so we’re talking about using a medication called lidocaine. I actually even use lidocaine as an abortive, so particularly it can be compounded and used as a nasal spray, as needed for women with migraines. We know there’s lots of safety data with lidocaine during pregnancy. 

So in this slide, procedures that can be done are nerve blocks and trigger point injections. The most common tend to be at the base of the head, or the greater and lesser occipital nerves. This can also be helpful for neck discomfort too, but trigger points are any areas of tightness or muscle tension, and not only can those areas be injected, but they can cause referred pain, and usually that’s in the head. So this procedure can be done in a serial fashion to also prevent migraines, so serial meaning every few weeks. It really depends on the woman and how long the effects last. 

Sometimes also we just really need to get them out of that first trimester when they’re more likely to be debilitated, get them to where those estrogen levels plateau. 

OnobotulintoxinA, so this is not approved for during pregnancy. However, understanding the mechanics of this treatment, so this is Botox. It is here, this is a protocol used particularly for the prevention of chronic migraine, but it’s a large protein and unlikely to cross the placenta. There is also, knowing this is botulism, there has been some studies talking about or case reports of women who have had food poisoning. There is concerns for preterm labor.

However, this treatment has been out for many years, not just for the prevention of migraine, but also for other indications. And so there is some registry data, particularly listed here. There’s over 232 eligible pregnancies that were exposed, mothers were exposed to onabotulinumtoxinA, either before being pregnant or during pregnancy within those three months. And it looks like for the most part, it’s generally safe, so no fetal malformations or any increased risk of miscarriage, similar to the general population. 

And then what about long-term safety data? So 45 patients receiving particularly PREEMPT is used for the prevention of migraine. And these children were studied over nine years, and it doesn’t look like there’s been any outcomes that are concerning. 

So in my practice, it really comes down to how debilitated the mother is, and looking at those adverse maternal outcomes, and weighing the risk versus benefit here. Usually, it’s also done in combination with some of my maternal-fetal medicine colleagues to make sure we’re all on board, who would be a candidate for this treatment. 

So there are some newer therapies out there, so calcitonin gene-related peptide therapies. It’s still fairly new, but there have been some safety reports. So in 2019, the World Health Organization put almost 100 safety reports, particularly looking at the injectable monoclonal antibodies. And as of right now, it doesn’t look like there’s any major safety concerns. Again, that’s a very small number and needs to be more long-term safety data. But it’s promising that there is registry data out there. 

Also looking at the smaller molecule, CGRP, Rimegepant, looked at with 12 women postpartum, and they were using this treatment as abortive with breastfeeding. And the levels were very, very small in the breast milk, so felt pretty comfortable, and there was no safety concerns at that point.

Still take home, need more information. And the way to get that is from case study reports and registry data.

And these are the non-medication devices that are approved for migraine. I like to point out that none of them have been studied in pregnancy or breastfeeding. On the left is the Cefaly device. This is an external trigeminal nerve stimulator. Right to the right of that is the single-pulse transcranial magnetic stimulator. In the middle here is the gammaCore device. It’s a vagal nerve stimulator. And then Relivion, it’s almost similar to the external trigeminal nerve stimulation, but it also combines the occipital nerve as well. And then the Nerivio device is an armband, and it’s a remote electrical neuromodulator.

So there’s some registry data on these devices as well, including here the Nerivio device. So there was a retrospective control survey study included 59 pregnant women using this device, and it looks like relatively safe. But again, we need some more information.

In my practice, general consensus is it is safe to use these treatments, but as long as there’s no contraindication to the device itself. For example, more common contraindications to neuromodulators are uncontrolled seizures, implantable cardiac devices, et cetera.

So to wrap up, migraine is common in women during their reproductive years. The majority of women will experience improvement in migraine, so that’s exciting. But it’s still important to treat these women, even if they continue to have migraine. If anything, I would advocate that this is essential to their prenatal care. 

Early open dialogue is key, if possible, preconception counseling with looking at more optimizing the lifestyle and nonpharmacological treatments. Although medication safety is not well studied in this population, there is still evidence to support the use of both acute and preventive treatments when needed.

And then you don’t want to forget to screen for any red flags during pregnancy and postpartum, particularly not missing any headaches that are associated with increased morbidity and mortality requiring emergent evaluation and treatment. 

And also migraine treatment, for the most part, is compatible with breastfeeding. There are safety databases publicly available to help in the decision making, and I will share those in the next slide.

And then there’s new emerging safety data on the treatment of migraine during pregnancy and breastfeeding, but these usually can be found through specialty organizations, experts, and rely on your national registries as well. I haven’t included the registry here in the states, but of course each country has their own. And that just shows you what’s up to date, you know, and the way these registries work is you have to enter that data in. 

So if you have a patient who is pregnant or, you know, things happen, we want to monitor and see, you know, see what those outcomes may be. 

So on this slide here are resources, particularly the first three are more resources for medications and reviewing the safety data, particularly with breastfeeding. And then also is registry data.

And the last two resources, Curable and Expectful, are more addressing the risk factors that contribute to progression of migraine and making sure they feel well supported more from the lifestyle standpoint.