Introduction

Background

Headache, one of the most common symptoms in the general population, is also common during pregnancy. Primary headaches are conditions where the headache itself is the disorder. In contrast, secondary headaches are caused by an underlying disorder, such as stroke, venous thromboembolism,^{1, 2} and pituitary tumors.^{3, 4} Management of secondary headache in pregnancy generally targets the underlying disorder, and, thus, is not the focus of this systematic review (SR).

Primary headaches that occur in pregnant women are classified into four types: migraine, tension headache, cluster headache, and other trigeminal autonomic cephalgias (TACs).⁵ At the end of Appendix A, we have provided a glossary of terms and abbreviations used in this report. The lifetime prevalence of migraine disorder among pregnant women is approximately 30 percent.^{6, 7} While tension headaches are most common in pregnant women in the population, migraine is by far the most common primary headache for which pregnant women seek care, accounting for about 90 percent of visits for primary headaches.² Tension headache is a less common reason for seeking care, and cluster headache and other TACs are rare.⁸ Primary headaches can be pre-existing (i.e., they began before pregnancy) or can occur for the first time during pregnancy, postpartum, or while breastfeeding. The stress of pregnancy and imminent infant care may exacerbate the frequency and/or severity of primary headaches.

Both pre-existing and pregnancy-onset primary headaches can have significant consequences for the mother, the fetus/child, and mother-child bonding.⁸ In addition to the symptoms themselves, primary headaches can lead to social consequences, including reduced productivity, loss of employment, financial detriment, and impacted family life, and clinical consequences, including depression, spontaneous abortion, preterm birth, and low birth weight.⁹

Although outside of pregnancy migraine frequency and severity often vary with a woman’s menstrual cycle, during pregnancy the course of migraine frequency and intensity can be more variable. In some cases, hormonal fluctuations can precipitate attacks of migraine and can make them more severe,^{10, 11} while in others, elevated estrogen and endogenous opioid levels can improve migraine symptoms and/or reduce their frequency.^12–14

Management approaches for primary headaches may harm the fetus and breastfed newborn. From a diagnostic standpoint, radiation and/or contrast agents (primarily neuroimaging) may harm the fetuses of pregnant women.^15–17 From a treatment standpoint, decisions during pregnancy, postpartum, and breastfeeding need to be made after consideration of both potential benefits and harms, which poses major decisional dilemmas. Regarding treatment for acute attacks of migraine, many of the commonly-prescribed drugs with the highest level of evidence in the general population can be harmful during pregnancy. For example, nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to be associated with a higher risk of spontaneous abortion (when used early in pregnancy) and of developmental malformations in the fetus, such as premature closure of the ductus arteriosus and oligohydramnios (when used in the third trimester).¹⁸ Similarly, sodium valproate, a commonly-used antiepileptic drug for prevention of migraine attacks, is contraindicated in pregnancy due to its teratogenicity and adverse neurocognitive outcomes in the offspring.^{19, 20}

Other therapies used outside of pregnancy, such as complementary and alternative therapies and biologic drugs (e.g., monoclonal antibodies), have unclear and/or mixed safety profiles during pregnancy and lactation. Therapies that are commonly used in patients with migraine during pregnancy include pharmacologic therapies, such as acetaminophen, antihistamines, caffeine, and magnesium. The first-line agents used for prophylaxis (i.e., migraine prevention) are beta blockers, such as metoprolol; low-dose tricyclic antidepressants, such as amitriptyline; and oral magnesium supplements.²¹ Metoclopramide, alone or in combination with other therapies, is frequently used for treatment of acute attacks, particularly in inpatient and emergency settings.^22–24 While other pharmacologic agents, such as low-dose aspirin and intravenous magnesium, that were used in the past are now less frequently prescribed. Other nonpharmacologic interventions for treatment and prophylaxis include hydration, physical therapy, and acupuncture. Pericranial nerve blocks, including occipital nerve blocks, are also increasingly used for treatment and prophylaxis against headaches in pregnancy.²⁵

Management of the other types of primary headache also presents decisional dilemmas. While patients with tension headache respond best to NSAIDs, they can be treated with acetaminophen, although often with only moderate success. Because cluster headache and other TACs are rare and inadequately studied during pregnancy, little is known about ideal treatments and prophylactic strategies for them. While some subtypes of TACs, such as paroxysmal hemicrania, hemicrania continua, and primary stabbing headache, respond to indomethacin (an NSAID), this drug is contraindicated in the latter phases of pregnancy. Little is known about nonpharmacologic treatments for primary headaches during pregnancy.

Unique aspects of the pregnancy and postpartum phases present challenges for managing primary headaches. Given the heightened sensitivity about the impact of pharmacotherapy on the developing fetus or breastfed infant, there is a tension between treatment decisions that might be best for the mother’s health and those that might be best for the fetus/infant. Regardless of treatment, migraine during pregnancy has been shown to be associated with various adverse maternal outcomes, such as preeclampsia, hypertension, pulmonary embolism, stroke, myocardial infarction, unplanned cesarean section, and adverse neonatal outcomes, including preterm birth, low birth weight, and respiratory distress.⁹ Sound risk-benefit assessments that optimize the health of both mother and fetus/child require clinical expertise and careful shared decision making between providers and patients.

The stresses on women during pregnancy and the ethical challenges in designing studies in this population have been obstacles to conducting studies to identify the most effective and safest therapies for these women and their offspring. Uncertainty about the comparative effectiveness and harms among various treatment options has meant that specific clinical practice guidelines for management of primary headaches during pregnancy do not exist. Existing guidelines on perinatal care from organizations, such as the American Academy of Pediatrics (AAP) and the American College of Obstetricians and Gynecologists (ACOG), do not discuss primary headaches.²⁶ Existing guidelines on the management of headache from the American Headache Society (AHS) do not discuss pregnancy.^27–29 To address the gap related to the overlap of primary headaches and pregnancy, ACOG nominated this SR.

Purpose and Scope of the Systematic Review

This SR assesses the prevention and acute treatment of primary headaches during pregnancy, postpartum, and breastfeeding. Specifically, the SR assesses: (1) the (comparative) benefits and harms of pharmacologic and nonpharmacologic interventions to prevent attacks of primary headache in women who have a history of primary headache and are pregnant (or attempting to become pregnant, i.e., in the preconception phase), postpartum, or breastfeeding; and (2) the (comparative) benefits and harms of pharmacologic and nonpharmacologic interventions to treat acute attacks of primary headache in women who are pregnant (or attempting to become pregnant), postpartum, or breastfeeding. The intended audience for this SR includes guideline developers, clinicians, and other providers of care for women with primary headaches and are pregnant, postpartum, and breastfeeding. ACOG nominated the topic of this SR. The findings of this SR are intended to be used in development of ACOG clinical guidance.