Migraine patterns in women are closely linked to various reproductive stages. During puberty, migraine prevalence becomes more pronounced in females compared with males, and remains so throughout the remaining life span. An estimated 40% of women experience migraine during the reproductive life cycle, and one-fourth of reproductive-aged women suffer from migraines.¹ Up to 70% of female migraine patients report changes in headache frequency or severity during menstruation, hormonal contraceptive use, pregnancy, and menopause.¹

A particular challenge in this population is the effective management of migraine during pregnancy and lactation while minimizing the risk for harm to the fetus. For many women with migraine, the frequency, intensity, and duration of headaches improve during pregnancy. Some research has shown similar effects with lactation, although findings have been mixed overall.²

In a recent paper published in Current Pain and Headache Reports,² Simy K. Parikh, MD, from the Jefferson Headache Center at Thomas Jefferson University in Philadelphia, Pennsylvania, reviewed evidence pertaining to preventive and abortive therapies for migraine during pregnancy and lactation.² Her findings are highlighted here.

Preventive treatment during pregnancy

• Among nutraceutical options, findings suggest that riboflavin (400 mg/day) and coenzyme Q10 (100 mg 3×/day) may be effective in preventing migraine if initiated 3 months before pregnancy.
• Anticonvulsants, including valproic acid and topiramate, should generally be avoided because of demonstrated risks for cognitive and motor impairment and for congenital birth defects, respectively.
• Among beta blockers, atenolol has been linked to low birth weight when used during the first trimester. The use of other beta blockers warrants close fetal monitoring for issues such as bradycardia and intrauterine growth retardation.
• Tricyclic antidepressants are associated with cardiac and craniofacial malformations, whereas serotonin-norepinephrine reuptake inhibitors have not been linked to these outcomes.
• Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be avoided during pregnancy. Use of these agents in the second and third trimesters may lead to pulmonary, renal, and skull malformations. Evidence for use in the first trimester is inconclusive.

Abortive treatment during pregnancy

• As prostaglandin synthetase inhibitors, nonsteroidal anti-inflammatory drugs increase the “risk for premature closure of the ductus arteriosus during use in the third trimester and are therefore contraindicated during that time,” whereas a recent study reported no adverse effects with the use of ibuprofen during the first trimester.²
• Findings indicate that metoclopramide is safe for use in pregnancy, including during the first trimester.
• No significant adverse outcomes were noted in a prospective observational cohort study of 432 pregnant women taking triptans.³ As sumatriptan has the most supporting evidence, this is the recommended option among the triptans.

Preventive treatment during lactation

• Topiramate is likely safe for use during breastfeeding, whereas valproic acid should be avoided.
• Propranolol is the preferred beta blocker for use during lactation because of its low maternal plasma levels
• With maternal use of tricyclic antidepressants, as “active metabolites are secreted into breast milk in small amounts[, infants] should be monitored for sedation, poor feeding, and anticholinergic side effects.”²
• Although angiotensin-converting enzyme inhibitors and angiotensin receptor blockers do not generally transfer to human breast milk in significant amounts, there have been concerns about renal toxicity when used in premature infants.

Abortive treatment during lactation

• Ibuprofen is the preferred nonsteroidal anti-inflammatory drug, based on studies showing very low levels of the drug in breast milk, even with frequent doses.
• Naproxen has been linked to drowsiness and vomiting in infants.
• Aspirin should be avoided because of the associated risk for Reye’s syndrome.
• Sumatriptan and eletriptan have low concentrations in breast milk.

“It is important for clinicians to think critically about pharmacologic options, as medications misattributed as teratogens or as a lactation risk could lead to poor treatment of episodic migraine in pregnancy, while use of true teratogens could lead to unnecessary exposure,” Dr Parikh concluded.²

To get a better idea of current treatment trends in this population, Neurology Advisor conducted a roundtable discussion with several experts across neurology and headache medicine, as well as women’s health: Teshamae Monteith, MD, a neurologist at the University of Miami Health System n Florida, and a member of the American Academy of Neurology; Huma Sheikh, MD, assistant clinical professor of neurology at Mount Sinai Beth Israel, New York City; and Paru S. David, MD, FACP, NCMP, assistant professor of medicine in the Division of Women’s Health-Internal Medicine at Mayo Clinic, Phoenix, Arizona.

Neurology Advisor: What are some of the challenges of treating migraine in patients who are pregnant or lactating?

Dr Monteith: The majority of patients with migraine without aura actually improve during pregnancy, but some may worsen, especially if they have to be taken off their migraine-preventive treatments. The biggest challenges are the lack of safe and effective treatments for pregnant patients.

Dr Sheikh: The main challenge is providing effective relief that is not harmful to the developing fetus. Trials usually exclude pregnant women; therefore, there is little information about which therapies are safe to use in pregnancy. Most of the evidence is based on observational trials. There are few treatments that have a level A rating for women who are pregnant or breastfeeding.

The other challenge is making sure that a headache is a primary headache caused by migraine or tension-type headache and not a symptom of another more dangerous disease, as pregnancy can increase the risk for certain disorders, including clots and stroke.

Dr David: Very little research has examined which medications are safe to use for migraine treatment during pregnancy and lactation in humans. Most medications have safety labeling based on animal studies, but many medications require a risk/benefit analysis because fetus or infant risk cannot be ruled out. Many clinicians who take care of pregnant or lactating women who also have migraine headache may not feel comfortable in deciding which medications are safe, either because they are not experts in migraine (obstetricians) and are unfamiliar with many of the migraine medications or because they are not experts in female hormones and their effects on migraine throughout the reproductive years of a woman (neurologists). 

Acetaminophen has been thought to be safe in pregnancy, but some recent research has questioned this, so now the recommendation by the US Food and Drug Administration is that a risk/benefit analysis needs to be performed. It does appear to be safe in lactation. Nonsteroidal anti-inflammatory drugs were felt to be safe in the first and second trimesters, and unsafe in the third trimester, but recent studies have shown possible harm in the first trimester, so now the recommendation is to do a risk/benefit analysis.

Neurology Advisor: What appear to be the best treatment options for these patients?

Dr Monteith: Metoclopramide and acetaminophen can be used safely. More recent large observational studies suggest sumatriptan is safe during pregnancy, and little drug gets excreted in breast milk. 

Nonpharmacological treatments such as aerobic exercise, cognitive behavioral therapy, biofeedback, acupuncture, and relaxation techniques may be effective for migraine prevention. Increasing evidence suggests nerve blocks may be effective and are safe during pregnancy.

Dr Sheikh: The first line of treatment should be ways to avoid known headache triggers, including poor sleep or stress. Stretching exercises and mild yoga tailored specifically for pregnant women can be helpful in preventing migraine attacks. Other approaches such as a warm compress or resting, especially sleeping, can be helpful and a way to avoid taking medications. Complementary methods such as relaxing breathing exercises or mindfulness can also provide great relief and are more likely to be effective if they are used as a daily practice or as a preventive.

In general, most medications should be avoided if possible. However, if needed, a large registry now shows that triptans are safe to use in women who are pregnant, although it is still important for physicians to consider other alternatives and whether triptans are safe in each situation.

Dr David: Healthy lifestyle changes such as regular meals, adequate sleep, stress management, trigger avoidance, exercise, and smoking cessation may reduce the frequency of migraine attacks during pregnancy. Biofeedback and relaxation are safe and beneficial for pregnant and nursing women.

Neurology Advisor: What are additional recommendations for clinicians?

Dr Monteith: Clinicians should emphasize lifestyle modifications including good sleep, stress management, and regular meals. Pregnancy planning should include a plan for migraines. Good communication between obstetrics/gynecology and neurology early on may lead to the best success.

Dr Sheikh: Most headaches during pregnancy will be primary headaches, but they can still be disabling. It is important to discuss the possible worsening of headaches before getting pregnant to set up strategies to help alleviate possible anxieties. It is important to work on healthy lifestyle techniques that are very effective at preventing headaches.

Always look for red flags in women with worsening headaches, so that a dangerous secondary headache is not missed. Thankfully, for most women, their migraine attacks improve during the second and third trimester, most likely as a result of stable hormone levels, but they can worsen again during the postpartum period. [Editor’s note: A prospective study published in 2003 reported that up to 83% of female migraineurs experienced a reduction in migraine frequency during the second trimester.²]

Neurology Advisor: What should be the focus of future research in this area?

Dr Monteith: Studies are needed to determine the safety of exposure to calcitonin gene-related peptide monoclonal antibodies for migraine prevention during pregnancy. In addition, evidence-based guidelines are needed.

Dr David: Exploring nonpharmacologic ways to manage migraine headache could be helpful because to date, no randomized controlled studies looking at the effects of migraine medications have been conducted on pregnant or lactating women, or likely will be, for ethical reasons.

References

1. Faubion SS, Batur P, Calhoun AH. Migraine throughout the female reproductive life cycle. Mayo Clinic Proc. 2018;93(5):639-645.

2. Parikh SK. Unique populations with episodic migraine: pregnant and lactating women. Curr Pain Headache Rep. 2018;22(12):80.

3. Spielmann K, Kayser A, Beck E, et al. Pregnancy outcome after anti-migraine triptan use: A prospective observational cohort study. Cephalalgia. 2018;38(6):1081-1092.