Episode 30: How Hormones Impact Migraine Part 2





Voice-over: Welcome to Spotlight on Migraine, the Professional Series, a podcast hosted by the Association of Migraine Disorders. In the Professional Series, we dive deeper into migraine-related topics with the help of guests from the medical field. The content of these episodes is intended for medical professionals but may be useful or interesting for patients as well. 


This episode is brought to you in part by our generous sponsors, Amgen, Novartis, and Alder BioPharmaceuticals.


In this episode, we hear more about the relationship between hormones and migraine over the course of a woman’s life. Neurologist Dr. Janet Waters discusses migraine and other causes of headaches during pregnancy, including medications used and their side effects. Dr. Mary Angela O’Neal continues by discussing the differential diagnosis of secondary headache in the postpartum period, as well as migraine treatment options during lactation. Lastly, we hear from Dr. Marcie Richardson, who explains the role of hormones in migraine during perimenopause and menopause, as well as the use of hormonal contraception to manage migraine in perimenopausal women.


Since 2015, Amgen and Novartis have been working together to develop pioneering therapies in Alzheimer’s disease and migraine. Together, Amgen and Novartis share in a mission to fight migraine and the stereotypes and misconceptions surrounding this debilitating disease.


Dr. Janet Waters: Okay, I want to thank you for inviting me. This is a great honor. So I work at Magee-Womens Hospital at the University of Pittsburgh, and I am the sole neurologist there. They have 9,000 deliveries per year. I also run the OB neurology service, and in both of those settings, the most frequently — complaint that I’m called to see is headaches. So this is a subject that’s near and dear to my heart.


So during the first trimester, it’s a perfect storm for migraines. Women are nauseous. They’re vomiting. They’re dehydrated. They’re not sleeping well at night. And so oftentimes, either they’ll maintain the same frequency of migraines, and sometimes, it will even worsen. But here’s the good news: once you get them past the first trimester — and it’s not exactly — sometimes, it’s about, I’d say, 16, 17, sometimes 18 weeks — as the nausea and vomiting resolve, oftentimes, the headaches get better. So in 70% of women, migraines actually improve during the pregnancy, about 5% actually worsen, and the remainder have no changing.


And improvement is more likely, interestingly, in women with menstrual migraine because they’re not having that fluctuation anymore. They’re not having menstrual periods, but for reasons we don’t understand, it’s less likely in women who have migraine with aura. So I love this slide. Okay, the tall blue bars, those are the women that actually achieved either remission or improvement in their headaches, and what’s interesting is, as you see the estradiol levels rise, so does the level of improvement. Now, after delivery, estradiol, as well as progesterone, drops precipitously, and migraine headaches will increase in frequency. And Angela’s going to talk to us more about that in the next talk.


So what are the risks of migraine on pregnancy? And there are several. So in all migraineurs, there’s an increased risk of gestational hypertension, preeclampsia and eclampsia, ischemic stroke, MI, as well as thrombotic events. Now, in the general population, primary headaches are the source of headaches in 90% of the population. So in that group of people, if somebody comes in with a headache, chances are 90% that’s a primary headache and not a secondary headache that’s much more worrisome. But in the pregnant population, it’s very different. In the pregnant population, only 65% of women presenting with headaches are having a primary headache. The other 35% have secondary headaches, headaches from something that’s much more worrisome. So when a patient comes in who’s pregnant with a headache, you’ve got to treat her much more carefully than a woman who’s not.


So let’s talk a little bit about the secondary headaches, and the reason being — whenever we talk about secondary headaches in a lecture on migraines, let’s be sure it’s a migraine before you start treating for a migraine, because some of these other types of headaches can be very serious. So I’m going to talk a little bit more, particularly, about preeclampsia because that’s one of the most common pregnancy-related secondary headaches. We’ll talk about venous sinus thrombosis; hemorrhagic stroke, briefly; and idiopathic intracranial hypertension.


Preeclampsia with severe features — let’s talk a little bit about this. These women will present with headache kind of all over. It can be throbbing in quality. They’ll have light sensitivity, nausea, and visual changes. Well, doesn’t this sound an awful lot like migraine? So how do you differentiate? First of all, preeclampsia, it’s very common — 2 to 8% of pregnancies. If it’s before week 20, you can pretty much rule it out. If it’s after week 20, and particularly as you get closer to delivery, you’ve got to really worry about this. So the most simple definition of preeclampsia is hypertension, proteinuria, and edema; and then if you add seizures to it, then it’s called eclampsia. 


So when a patient presents with a headache, one of the first things you want to do is ask what the blood pressure is. Oftentimes, in very severe cases of even — not necessarily eclampsia, but even severe preeclampsia, you can develop what’s called PRES, posterior reversal encephalopathy syndrome. So this is basically brain edema, and so this is classic for the PRES that we oftentimes see associated with pregnancy. And these women will come in with visual complaints, and it’s related to edema in the occipital lobe. So when you look at their MRI, you’ll see fluffy stuff in the occipital lobes, usually bilaterally. In very severe cases of PRES, and this is basically like hypertensive encephalopathy with global brain edema, then you can see any lobe of the brain involved.


This is something that I think we’re picking up more frequently, cerebral venous thrombosis, and I think one of the reasons why we’re picking up on it more is because of our new imaging techniques. So we now have MR venogram, and MR is safe to do in pregnancy, so oftentimes, we’re picking this up more nowadays than I think I did earlier in my practice. So basically, this occurs most often in the third trimester of pregnancy, and you think about it: the natural way — nature’s way is to make women hypercoagulable before delivery and even for a period of time after delivery. So some women can develop a blood clot in the veins. In the early stages, they can come in with blood clot in the brain, and the only symptom will be headaches, so that’s pretty scary. So you’ve really got to make sure that you capture these patients. If left untreated, they’ll go on to form venous infarcts in the brain, and that’s when they’ll develop focal deficits, seizures, sometimes a hemorrhage into their infarcts; and it can be devastating.


So, far less common, the preeclampsia occurs in 1 per 2,500 to 10,000 pregnancies, and oftentimes, what we find out with these women is they had an unrecognized hypercoagulable disorder, and then you throw the pregnancy on top of it, and that combination is enough to form a cerebral thrombosis. 


And I’d like to talk next a little bit about idiopathic increased intracranial hypertension because this can also oftentimes be confused with migraines. It occurs in women of childbearing age, and it’s associated with rapid weight gain. The literature will tell you it’s no more common in pregnancy than in non-pregnant women. My experience is we see an awful lot of it, and these patients will also present with a diffuse headache. It tends to be worse when they awaken. They can have double vision. They can have blurred vision. Classically, they’ll have papilledema, but if a woman doesn’t have papilledema, it doesn’t necessarily rule it out. So if we have a high suspicion for this case, and we’re trying to differentiate, “Is this migraine or is this something more worrisome?” then we will do a spinal tap on these patients. You can’t do this under fluoroscopy. It has to be done at the bedside.


So let’s get back to our initial purpose here, talking about migraine and pregnancy. When you think about the drugs that we use to prevent migraines in most patients — and they can be a real problem with your pregnant population. So beta blockers — some people use them, but they have been known to cause neonatal bradycardia. I know our obstetricians at Magee prefer that we avoid them. Amitriptyline — some people are using it, and in low doses, it’s probably safe. But even in this group, in the last 4 weeks of pregnancy, it’s best to discontinue this because the baby will sometimes get jitteriness and some drowsiness and sometimes difficulty with feeding. Topamax causes increased risk of cleft palate. Valproate — I don’t prescribe that to anybody over the age of 12 [laughter].


So what do we do to prevent migraine in our pregnant patients? Well, this is non-pharmacologic things, things that most of you are very familiar with, basically, healthy lifestyle, and I think the most important one here is the exercise. And so I really encourage my patients to maintain their exercise levels throughout the pregnancy. Secondly, magnesium — it’s safe to use in pregnancy. It works. I usually give doses 250 to 500 mg daily. Some of our obstetricians will use 400 twice a day, but the side effects are diarrhea, so I usually stick to the 250 to 500. Other options — if you have a headache clinic available that does this, and we do, you can do peripheral nerve blocks. And then if there’s a component of depression with it, then you can use some of the safer antidepressants as well. 


So what do you do to treat the migraines when they do occur? Again, we’re so limited. Non-steroidals — we want to avoid use in the third trimester due to the risk of premature closure of the fetal ductus arteriosus. Opiates — I don’t think they have any role in migraines, period. It’s bad enough in the regular population. You have a patient who has migraines, you treat them with opiates, and then they have two problems because then they have a dependence. Even worse in a pregnant patient because the baby will go into withdrawal after delivery. Butalbital — it’s associated with teratogenicity, neonatal withdrawal. Ergots — absolutely contraindicated due to the increased risk of miscarriage.


So let’s talk just for a couple of minutes about triptans, because this is fairly controversial. Now, there was done this meta-analysis study with over 4,200 patients that were exposed to triptans during pregnancy. I think we can all feel pretty comfortable that there’s not a risk of teratogenicity, but there was in this study an increased rate of spontaneous abortions. Now, another study came out more recently, but it’s a lot smaller, 432 women. This was done in Europe, and again there was no risk of birth defects, so again, I think we can feel comfortable with that. Now, they found no increased risk of spontaneous abortions, so what do I do? In my practice, I avoid them, and for the most part, I can get my patients through pregnancy. And I’ll talk a little bit about the way I treat that next. But that being said, in our headache clinic, where they see some of the worst migraineurs you can imagine, sometimes, they just go ahead and use the triptans because there’s no other way to keep these women comfortable during their pregnancy.


So, what do I do? A patient lands in my ER at Magee, and she’s got severe headache. She’s got nausea. She’s got vomiting. She’s got photophobia, phonophobia, osmophobia. First thing I do is I hydrate the mom because oftentimes they’re dehydrated, and then I give what’s called our version of — a pregnant version of a migraine cocktail, so that consists of Compazine, Tylenol, and Benadryl. I give it IV all in one dose. If she gets better, terrific. I send her home, providing she has a normal neurologic exam and a normal blood pressure. If she doesn’t get better after the migraine cocktail, especially if she’s after 20 weeks, I go ahead and image them. So I’ll do an MRI, MRA, MR venogram, and if those are normal and she’s still having a headache, I’ll bring her in, and I treat with a migraine cocktail, every dose all given at once every 8 hours for 3 doses. Then if that doesn’t work, my next step is to go to magnesium 1,000 mg IV, q12 for 3 doses.


Thank you very much.




Dr. Mary O’Neal: So my objectives today. I would like to discuss really briefly some of the differential diagnosis of headache in the postpartum period because this is actually the danger zone. Janet Waters outlined very clearly the numbers of headaches that we see, but I’ll just sort of go through from a different perspective the red flags, and then examine the best migraine treatment during lactation.


So we look at primary versus secondary headaches, and I could have made this pie a little bit different, but most of the time we’re talking about primary headache disorders. But in the postpartum period is really when you’re concerned about many secondary headaches, and the headaches that we’re concerned about are those that have to do with stroke, hemorrhage, dissection occurs at labor, certainly pituitary apoplexy can happen, cerebral venous thrombosis. 


In a study from our institution, Dr. Feske looked at a decade of deliveries, 100,000 deliveries. All the patients who had CVT, cerebral venous thrombosis, presented in the postpartum period. Your body, in order to deliver — you have a natural tendency to get — hypercoagulable state, but that hypercoagulable state actually lasts up to 6 to 8 weeks postpartum. So postpartum is actually the most dangerous time for cerebral venous thrombosis.


And then preeclampsia, eclampsia — you can have that postpartum as well, and then [inaudible] reversible cerebral venous constriction syndrome is a overlap syndrome with preeclampsia and, again, is a very dangerous diagnosis. We do not see — idiopathic intracranial hypertension, actually, is cured by delivery because you’ve lost a lot of weight, so.


So here’s sort of my view of what happens with headaches in pregnancy. So I’m fortunate to have an embedded neurology clinic with my maternal-fetal medicine colleagues. And my clinic is filled in the first trimester with headaches, and then, as Dr. Waters explained, most of those patients, 80% of them, go away, and then when do I see them back? Postpartum. So one nice study, actually, from our institution — one of our headache fellows looked at patients — women who presented with acute headaches in the postpartum period, and over 75% of those patients had a secondary headache syndrome, of which at least 50% was related to eclampsia and cerebrovascular disease. So it’s really the postpartum period which is the most diagnostically challenging. So if you see a patient with a new headache disorder and that does not correspond with a low-pressure headache, they should be imaged.


Historical features — I think Dr. Waters outlined this nicely, but I’ll just — a couple just quick points. So thunderclap onset, that is, maximum onset at time of headache onset. We always think about subarachnoid hemorrhage, but in this population, cerebral venous thrombosis, reversible cerebral vasoconstriction syndrome should also be thought of. 


Postural headaches — obviously, if their headache gets worse when they stand up, we’re thinking about a low-pressure headache, and if they get worse when they lie down, we’re thinking about the other — opposite — elevated intracranial pressure. In postural headaches, we don’t usually image, but if there’s some diagnostic uncertainty, I think MRI with a contrast can be very helpful. And we’ll see the leptomeningeal enhancement, the enlargement of the pituitary, the sagging brain, and in severe cases, subdural hematomas. If they have a similar headache syndrome — so the one question I’ll ask my patients is, “Is this like your usual headache?” If the answer is yes, ooh, I’m all done. If it’s no, then you have to pay attention. 


And then obviously, if we have hypertension and proteinuria, we will be concerned about preeclampsia and eclampsia. And even though the treatment for preeclampsia is delivery — as our obstetrical colleagues know that these changes that start at, actually, inception of pregnancy, at the time of implantation of the placenta — those changes can persist well into the postpartum period. And then MR, as Dr. Waters said, we can see the posterior reversible encephalopathy syndrome. 


So what about the epidemiology? What happens to migraine after delivery? So Sances looked — followed women with migraine throughout their pregnancy and postpartum, and 34% of those patients would have — in the first week, would have recurrence of their migraine, and by the first month, at least 50 — over 50% would have recurrence of their migraine. Another large study in a Japanese population looking at women postpartum — they showed that by 1 month, over 50 to 60% of them will have recurrence of their migraine. 


Breastfeeding seems to be protective, and in every point that looked at in this study — 1 month, 3 month, and 6 months — those women with migraine who were breastfeeding, they had a lower incidence as compared with women who were not breastfeeding. And then we don’t really know, but it may be related to lactational amenorrhea, going back to what Dr. Hessler’s talk was about.


Triptans are considered safe in the postpartum period. Less than 3% is excreted into breast milk. I think that we have the largest experience with sumatriptan, but they look like they’re very safe. They’re certainly very effective, and multiple of our preventative medicines are also considered safe. This website, Lactmed, is a nice reference. I’m just going to remind you there’s classifications of pregnancy safety — or, excuse me, breastfeeding safety, L1 being the hailed most safe, and L5 is that this medication is contraindicated with breastfeeding. 


So of the symptomatic medicines that we use, non-steroidals, which are quite effective, are very safe. Metoclopramide is also extremely safe, as is magnesium. Triptans — they have a L3 rating, but I think that the American Academy of Pediatrics has considered them very safe in breastfeeding. And then we would avoid the ergots, and we would try to avoid codeine and butabarbital. 


Of the preventative medicines, we have lots of choices. Of the beta blockers, I think propranolol would be the first choice because it’s quite safe. Anti-epileptic drugs — gabapentin is quite safe but not as effective as a migraine preventative, and then the tricyclics are quite safe, and we would use those as well as verapamil.


So in summary — I’m trying to stay on my time line here — secondary headaches are common in the postpartum period, and you need to have a heads-up and be aware of that. Migraine is often exacerbated in this time period because of fluctuating hormone levels as well as sleep deprivation and stress. And there’s both very safe symptomatic and preventative medications during breastfeeding.


Dr. Marcie Richardson: I thank the organizers for inviting me, because now I know more about migraines than I started out. So I’m going to talk briefly about menopause and migraine, and I just want to point out that migraines are more prevalent in women than men. We’ve seen some information about epidemiology, which I’m afraid some of it I’m going to repeat. Menopause is also very prevalent in women [laughter].


Migraine affects about 1/4 of perimenopausal women, and I think that we saw that very nicely in the woman on the left’s slides, who showed that peak of migraine activity in the late reproductive years. Interestingly enough, of women over 60, only about 6% report migraines, so we can all go home right now [laughter], but I have a few more things to say. So the risk — this interesting — one of the studies that was referred to earlier, where they were doing a survey of migraineurs, tried to look at the incidence of migraines over the menopause transition, and they posited that the risk for high-frequency migraines increased again during perimenopause, as we’ve mentioned, by 1.4, but the effect disappeared in menopause.


I think that’s what we know, and I actually think there’s a lot we don’t know about the history of migraines in the lifespan of women. I want to say a little bit more about definitions. This is the Stages of Reproductive Aging Workshop, and it’s an attempt to hone in on definitions of where women are in their reproductive lives, because as you try to study the various symptoms that women experience, perimenopause in particular has been a very fuzzy area. And many clinicians, if a woman comes in in her early 40s with a variety of complaints, will say, “Oh, no, this isn’t perimenopause. You’re too young.” Well, in fact perimenopause probably extends for about as much as 8 years. You could argue it starts in utero. because after all, the amount of eggs goes down dramatically throughout fetal life, but I won’t push that [laughter].


In any case, the first thing that women tend to notice in their late reproductive years is that their periods are coming closer together, so the poor menstrual migraineurs are getting more headaches. And then there’s menstrual irregularity, and there definitely is a cohort of women who develop new headaches. I was one of them. I never had headaches, and then in my 40s, I started to get them with my periods. And it actually took me about 2 years to figure out that that’s what was happening, and then I went on birth control pills, and then it stopped. But anyway, too much information. I’m sorry [laughter]. 


This is my absolute favorite graphic. This is some work that Nanette Santoro did and published in 1996, and look at it. You can see this is what reproductive hormones do during women’s reproductive years on the top, and on the bottom, postmenopause, you can see that we actually feel a bit more even. Our hormones are stable throughout the months, but look. This is one of Nanette’s relatives who collected urine every day for 6 months, and look what her hormones are doing. They’re really all over the map, and it’s extraordinary recognition that I see from my patients in perimenopause when I show them this graphic. They say, “Yeah.”


But the other couple of interesting things about this are that the estrogen level, which is the red, goes way higher than you see it during the reproductive cycles in some women. Also, that the progesterone sort of tapers off, and this is where I always mention what Brian Walsh said, which is, Doing hormone tests on a perimenopausal woman is like taking the picture of the speedometer when the car is in the garage [laughter]. You don’t know what it was doing 10 minutes before, and you don’t know what it’s going to be doing 10 minutes from now [laughter]. So actually, checking hormone levels on perimenopausal women isn’t really helpful in trying to sort out the diagnosis.


So migraine in menopause — the role of hormones. There’s not much data that I could come across about the correlation of hormones and migraines in any real detail, but Dr. Pavlovic — who’s a neurologist from Einstein, I think — did look at the SWAN study. And the SWAN study is a study of women across the nation where they studied women over the menopause transition, and they did a lot of hormone tests on them. And what she was able to show was that the absolute peak in day-to-day endogenous sex hormone levels were similar for migraineurs and controls, but there were significant differences in the rate of estrogen withdrawal that were phase-specific, in other words, during the late part of the cycle a couple of days after the peak of estrogen. And these differences occurred irrespective of whether migraineurs experienced headache within the cycle or not. So she posited that possibly women migraineurs have some special neuroendocrine vulnerability. This is interesting. More to come. But I thought it was worth mentioning an area that needs more study.


So let’s talk for a second about treatment. Perimenopausal women with menstrual migraines and no history of migraine with aura may benefit from continuous combined hormonal contraceptives until their mid-50s. This is a point I do want those of you who prescribe to take home, because I see women all the time who’ve been taken off their oral contraceptives prematurely, in my opinion. 90% of women will reach menopause by the age of 55, so women without contraindications — which would be hypertension and migraine with aura, primarily — can be continued on low-dose oral contraceptives continuously until their mid-50s. This is just a teaching point, but 20 µg of ethinyl estradiol that’s in combined oral contraceptives does deliver fourfold more estrogen than standard-dose hormone therapy, so theoretically, you would like to get a woman off of oral contraceptives when she gets to menopause.


So migraine and menopause — the use of hormone therapy. The 2017 NAMS, North American Menopause Society, position statement on hormones says that, For women aged younger than 60 years or within 10 years of menopause onset and have no contraindications, the benefit-risk ratio of hormone therapy is most favorable for the treatment of bothersome vasomotor symptoms. They could have said that more easily, that estrogen really is the best thing to treat vasomotor symptoms, and some women really suffer from vasomotor symptoms.


So what about women with vasomotor symptoms and migraine and the use of hormone therapy? Migraine with aura is not a contraindication for the use of replacement — and replacement is actually the wrong word, and I apologize for that. I noticed that this morning. For the use of estrogen therapy in the menopausal woman, it’s not really replacement, as I alluded to before. I do recommend using the lowest effective dose of non-oral estrogen that controls vasomotor symptoms — I’ll circle back to the non-oral piece in a minute — and I suggest that you start with .025 mg per 24 hours of an estradiol patch. Data supports the notion that transdermal estrogen does not have the thromboembolic risks associated with oral delivery, and this is a very important clinical point. We avoid the first-pass effect on the liver, which increases clotting factors. It also increases SHBG and other proteins, which may have adverse effects.


So now, this slide [inaudible] okay. This is a very recent study from the BNJ of — I mean, it’s an epidemiologic study. It’s not a randomized trial. You can see here, the forest plot shows the incidence of thromboembolic events, and I’ve circled transdermal where you can see it is on the negative side. So we do feel really comfortable using transdermal estrogen in women with migraine with aura. 


Just a comment about the progestogens. Where progestogen is required, continuous delivery is recommended for women with migraines, using either micronized progesterone or the levonorgestrel intrauterine system. I did want to make one point about that, which is that you can measure systemic progestogen in women who have the levonorgestrel IUD in. It’s not very high, but it is measurable. The data is limited on the dose and types of progestogens, and trial and error is always required.


Thank you very much.




Voice-over: Since 2015, Amgen and Novartis have been working together to develop pioneering therapies in Alzheimer’s disease and migraine. Together, Amgen and Novartis share in a mission to fight migraine and the stereotypes and misconceptions surrounding this debilitating disease.


Thank you for tuning in to Spotlight on Migraine. For more information on migraine disease, please visit MigraineDisorders.org.


This podcast is sponsored in part by Amgen/Novartis and Alder BioPharmaceuticals.

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