Doctor on Call: Migraine therapy during pregnancy
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Olivia, a 31-year-old environmental scientist who lives in Kensington, Maryland, writes…
Dear Doctor,
I just returned from seeing my neurologist, and I’m both confused and very alarmed. For the past two years she has been treating me for chronic migraine. After prescribing me multiple oral drugs that did nothing to help and often caused side effects that were worse than my headaches, she started administering Botox every three months. With Botox I was doing great! Rarely having headaches, and able to treat them easily when I did.
Anyway, suddenly and recently I found myself pregnant. My husband and I weren’t really trying to have another baby, but we weren’t really trying not to either. After I tested positive for pregnancy, I decided to skip my next Botox treatment, and within just two weeks of skipping that treatment I started having headaches all the time. I’m spending most of my time in bed or sitting in my bathroom trying not to vomit, and my head is throbbing so painfully I can barely think.
When I saw my neurologist today, she told me that the therapeutic effect of Botox had worn off and that I should be treated again as soon as possible. I thought she was kidding! Inject a neurologic toxin into me while I’m carrying a baby? No way!
Am I overreacting? Or is she crazy off-base?
— Pregnant with migraine in Maryland
The Doctor’s Reply:
Dear Olivia,
You are not overreacting. You are behaving like a good mom and watching out for the safety of your child. And your neurologist is not “crazy off-base”. She is attempting to reduce your migraine burden without exposing your baby to a known risk.
The path a given migraine therapy must travel to become regarded as “acceptable” for use – usually off-label use – during pregnancy is typically long and convoluted.
For example, as recently as 5 years ago, the author’s suggestion to obstetricians that continued use of onabotulinumtoxinA (BotoxA) for chronic migraine patients whose migraine had persisted into pregnancy and had worsened off BotoxA routinely was met by expressions of horror. In contrast, many obstetricians now accept such management as quite acceptable and refer their chronic migraine patients who are attempting to conceive or are newly pregnant to the author specifically for BotoxA therapy.
Why? Has there been conducted a well-designed prospective clinical research study that specifically assessed the risk to the pregnancy and fetus potentially conveyed by sequential BotoxA injection therapy for suppression of chronic migraine during pregnancy? No, there has not. The path to the neurotoxin’s acceptance for use during pregnancy has followed a familiar path, and one integral part of that path typically involves time. What might seem unthinkable when a new therapy emerges becomes less so as time passes and there is more and more experience with that therapy. BotoxA has been used for decades to treat various medical disorders, and 14 years have passed since Botox received FDA approval for the treatment of chronic migraine.
In parallel with time are pregnancy registries. Such registries typically are sponsored and maintained by the drug’s manufacturer, and they depend upon healthcare providers and their patients to report proactively clinical outcomes when there has been exposure to that drug during pregnancy, regardless of whether the exposure was intended or unintended. As such, pregnancy registries are susceptible to selection bias. Given that they depend on provider or patient inclination and initiative, they are not equivalent in scientific rigor to a carefully conducted prospective study that evaluates all pregnant females exposed to the drug. Even so, it is at least somewhat reassuring when there have been many thousands of such exposures reported and no signal indicating potential harm to the pregnancy or fetus has emerged. So has it been for Botox. And on the acute migraine treatment side, so has it been for sumatriptan, a medication available for use in the US since 1992.
Also helping to propel a therapy down the path to acceptance are published case reports and case series, the former involving single patients or small groups of patients and the latter assessing a larger group of patients. Especially compelling in the circumstance of female migraineurs exposed to Botox during pregnancy are 7 reported cases of pregnant females who suffered actual botulism poisoning during their second or third trimester and whose infants demonstrated no evidence of birth defects or clinical botulism; in one case wherein the mother had severe muscle paralysis, fetal movements were the only visible movements in her body. In one large case series of pregnant females treated with Botox that was published in the journal Neurology in May 2023 and involved over 900 pregnancy outcomes, the prevalence of fetal defect was 2.6%. For the general population that prevalence varies between 3 and 6%.
Finally, and particularly relevant in the case of BotoxA, there is basic pharmacology. The Botox molecule is large, and as was the case in the botulism suffered by the 7 pregnant females mentioned above, the molecule does not pass from mother to fetus in the placental circulation even when the mother’s blood contains concentrations of the neurotoxin far in excess of what is administered to treat chronic migraine.
BotoxA aside, there are a number of therapies for migraine prevention and acute migraine treatment that can be considered “acceptable” for use during attempted conception and pregnancy. In some cases there appears to be near-zero potential for harm to the fetus, and this group would include acetaminophen, devices such as Nerivio, occipital nerve blocks, and “supplements” such as riboflavin and magnesium.
In a thankfully small handful of therapies that have a strong evidence base for use in migraine and are FDA-indicated for such use, the risk to a developing fetus is so unacceptably great that their use is absolutely contraindicated if one is at risk of becoming pregnant or pregnant. The most important example is divalproex sodium (Depakote) a medication indicated for migraine prevention, epilepsy and treatment of bipolar disorder. Especially during the first trimester of pregnancy, exposure to Depakote may cause horrific problems with the development of the fetus’s brain and nervous system. Because women so often may not know they are pregnant during the first critical weeks of fetal development, no female at risk for pregnancy should take Depakote. Another widely used drug to be avoided if one is at risk for pregnancy is topiramate (Topamax), linked to a risk of cleft lip or palate.
In between these two extremes are a multitude of migraine treatments for which we have no clear evidence of risk to the pregnancy or fetus but also no definitive evidence of “no risk. For some, either because of their relative newness on the clinical scene, a theoretical risk associated with the drug’s mechanism of action or both, these are medications better avoided unless the clinical circumstances to support their use are compelling. For others the risk would appear to be minimal at most, and BotoxA falls squarely within this group.
Your concern is both understandable and commendable, but your doctor’s recommendation that you resume BotoxA is reasonable and clinically appropriate.
