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After completing this continuing education article, the pharmacist should be able to:
Migraine headaches are the most common vascular headache type and have a significant impact on quality of life and the health care system in the United States. Within the United States alone, approximately 13% of the adult population suffers from migraine, although others have reported more accurate estimates to be close to 30 million Americans with this disorder.1 Women are more commonly affected than men, with a prevalence of 18% and 6%, respectively. Approximately 70% to 90% of patients report having a family history of migraine.1-3 The importance of proper treatment cannot be overemphasized when looking at the economic impact of headaches.
Migraines affect people during their productive years (25-50 years of age), and the direct and indirect costs are a significant burden to society. Direct costs are reported to be close to $1 billion per year in the United States, and indirect costs from time lost at work, school, and home are estimated to range from $5.6 billion to $17.2 billion per year.1,4,5
Pharmacists are often on the front lines of care for migraine patients seeking relief from their headaches and are often in a position to direct the initial care and education for these patients. The importance of a thorough understanding of migraine and its management is essential for pharmacists, because as many as 57% of patients self-treat migraine headaches,6 and inappropriate use of OTC analgesics can increase the risk of medication overuse headaches (MOHs). By advising, educating, and instructing patients in the appropriate use of OTC analgesics in migraine, the pharmacist can be a valuable addition to the management team for this chronic disorder. Having the knowledge of how and when to use the OTC therapies and when to recommend further evaluation is important when interacting with headache patients seeking advice.7
Etiology and Pathophysiology
Numerous theories have been proposed to describe the pathophysiology of migraine. The most recent and widely studied theory involves the trigeminovascular system. This system appears to be under the influence of numerous triggers that activate the trigeminal afferent neurons in this system to cause the release of numerous vasoactive peptides. These peptides include calcitonin gene-related peptide, substance P, neurokinin A, and nitric oxide, which when released from the meningeal blood vessels result in inflammation, vasodilation, and plasma protein extravasation. The end result is inflammation, which influences the trigeminal nucleus caudalis in the brainstem (migraine generator) and cervical cord area and transfers pain data to upper areas of the brain (thalamus and cortex). This transfer of pain data is thought to result in the pain perception of migraine. Persistent pain in this system may result in a central sensitization or allodynia state, which describes amplification of sensory information from central neurons. This process may also be responsible for facial and neck pain experienced in migraine along with associated symptoms such as gastrointestinal and/or visual changes, eg, photophobia.
Former theories of migraine such as the vascular theory focused on alterations in cerebral blood flow; but this does not appear to be a consistent event in the pathophysiology of migraine. In addition, this theory cannot explain the premonitory or other symptoms of migraine. Further support for a more central cause is the usefulness of many central-acting drugs in the pharmacotherapy of migraine, which have little effect on the vascular system.8-10
Various neurotransmitters also play a role in migraine, including serotonin (5-HT), dopamine, glutamate, and gammaaminobutyric acid. Neurotransmitters are probably involved in the neurologic processes described above, and an imbalance in 5-HT and adrenergic neurons and pathways may be involved. Specific involvement with neurotransmitters may include disturbances of 5-HT regulation in the midbrain, a hypersensitive state to dopamine, and the involvement of glutamate release in the aura of migraine.10
Clinical Presentation and Diagnosis of Migraine
The clinical presentation of migraine can be variable, and diagnosis may require physicians experienced in migraine or those who specialize in this complex disorder. For this reason, many patients remain undiagnosed or are erroneously diagnosed as having sinus/tension headache, and these patients often self-treat with OTC medications.6,11,12 The clinical presentation of migraine may also have atypical manifestations, although many patients present with core clinical features. The Headache Classification Subcommittee of the International Headache Society (IHS) has developed a comprehensive system of classification for migraine that was updated in 2004.13 Although the IHS is the usual tool used to guide the diagnosis of migraine, other clinical tools are also used in clinical practice.13-15
The 2 common types or presentations of migraine include migraine with and without aura (Table 1), although other migraine types and variants are discussed in more detail in the published IHS classification document.13 The clinical presentation of migraine is defined in stages, with the preheadache phases described as the premonitory phase and the migraine aura. Premonitory phases may precede the headache by hours to days and may affect 20% to 60% of patients. Features of this phase include neurologic and psychological symptoms. The migraine aura manifests with more focal neurologic features, commonly described as various visual field changes. These symptoms usually precede the headache by 5 to 20 minutes and last up to 1 hour. In contrast to tension-type headaches, which tend to be bilateral, migraine headaches are usually unilateral but may become bilateral during the course of the headache and are aggravated by routine activity. Migraine pain is typically a throbbing, pulsatile pain in the frontotemporal region, whereas tension headaches are often described as dull or pressing pain involving the entire head. The duration of migraine attacks may vary and ranges from minutes to days, with the average falling between 4 and 72 hours. Pain intensity is classified as mild, moderate, or severe and may vary from headache to headache; in addition, pain often escalates over the course of the headache. Numerous other features may also accompany the headache phase, including gastrointestinal symptoms such as nausea and vomiting, and autonomic symptoms such as nasal congestion and lacrimation. The final phase of migraine occurs after the attack and is referred to as the resolution, or postdromal phase. This phase usually results in symptoms of fatigue and irritability for 1 to 2 days; this is sometimes referred to as the migraine hangover. Many female migraine patients experience their migraines in association with their menstrual periods, suggesting a hormonal component. Menstrual migraine (MM) is defined as attacks occurring approximately 2 days prior to menses and ending 4 to 7 days later.15 Many patients, including those with MM, can predict when their migraines will occur, and therapeutic approaches can be targeted to these cycles.15-18
Migraine Triggers and Associated Comorbidities
The therapeutic approach to migraine should always include an evaluation of potential triggers and/or precipitating factors so that the pharmacist can counsel the migraine patient to avoid or reduce exposure to potential migraine triggers. Dietary triggers may be patientspecific, although there is limited evidence to support dietary interventions. Foods that contain tyramine, wheat products, sugars, and milk products have all been reported by patients to cause or contribute to migraines. A good rule may be to suggest avoidance of foods that appear to exacerbate the patient's migraine without compromising nutritional status. Table 2 provides a comprehensive list of foods, chemicals, drugs, and physical and psychological factors that may precipitate or exacerbate migraine headaches. Some commonly discussed chemical precipitants include monosodium glutamate, nitrates and nitrites, tyramine, and phenylethylamine.18-22 Pharmacists should be aware of drug causes, including alcohol, nitroglycerin, and other vasodilators. Smoking has also been implicated in triggering headaches, with complete cessation usually recommended.20,21
Nonchemical triggers of migraine may include fatigue, excitement, stress, exposure to extreme cold or heat, glare from light, hay fever, and insomnia. Developing consistent sleeping patterns is an important nonpharmacologic therapy that may benefit patients with migraine.19 The complexity of migraine headaches leads to its association with numerous comorbidities. Migraine is associated with a wide range of neuropsychophysiologic conditions, including depression, bipolar disease, personality disorders, sleep disorders, obsessive-compulsive disorders, anxiety, epilepsy, stroke, dependency, vulnerability, and eating disorders.23
Managing the Patient with Migraine Headache
The initial assessment of patients with new-onset headaches should include a complete medical evaluation to rule out reversible causes, including rare serious causes such as tumor or cerebrovascular abnormalities. If migraine is diagnosed, patient management should explore the possibility of triggers or exacerbating factors and the use of appropriate therapy, both nonpharmacologic and pharmacologic.18,22,24
Actual management should begin with the education of the patient and family, because this disorder can have a significant impact on family life. The pharmacist should also suggest that patients develop a headache diary to document headache frequency, associations with various triggers, and response to pharmacotherapy.
Nonpharmacologic therapies include behavioral therapy and psychosocial interventions, including relaxation therapy, biofeedback, and stress management, all of which may be effective in some populations. Biofeedback, which is often combined with behavior modification, is designed to teach patients to handle stress. A typical course consists of 8 to 10 weeks of sessions lasting 30 to 45 minutes. The sessions may include activities that involve learning to control physiologic functions such as temperature, learning to relax various muscle groups, and learning breathing techniques. Biofeedback in combination with pharmacologic therapy is also effective in some patients.25-28 The use of acupuncture has revealed some beneficial trends in the management of headaches and may be an option in some patients.29 Other methods include applications of heat and cold, impulse magnetic-field therapy,30 and photic stimulation,31 and physical approaches such as aerobic exercise, isometric neck exercises, and chiropractic manipulations.32 The United States Headache Consortium (USHC) provides evidence-based information on the use of nonpharmacologic therapies in the treatment of migraine headaches.33 The guidelines are based on results of meta-analysis data, suggesting that cognitive- behavioral programs including stress management and biofeedback are effective in migraine prophylaxis.34 Additional meta-analysis data reported that biofeedback in combination with relaxation was similar in efficacy to betablockers in the prevention of migraine.35
Pharmacologic Treatment of Migraine
The pharmacotherapy of migraine headaches consists of abortive and preventive therapy.36,37 Abortive therapy involves pharmacotherapy for the acute relief of headache. These agents are used on a short-term basis, with restrictions on amounts used and length of therapy. Abortive therapy of migraine includes a number of prescription drug classes (Table 3)38-42 and OTC products (Table 4) that many patients use for self-treatment.11,12,36,40 The availability of OTC agents places the pharmacist in a position to provide valuable information on migraine and the appropriate use of OTC agents. This article will discuss the role of OTC analgesics in migraine and provide the pharmacist with some guidelines as to when to recommend them, limits to their use, appropriate choices, and when to recommend patients to seek further evaluation.
Preventive migraine therapy is intended to reduce the frequency and severity of attacks and improve or reduce disability. In addition, it should reduce or in some cases eliminate the need for abortive drug therapy. Prophylactic pharmacotherapy consists of daily administration of pharmacotherapeutic agents for periods ranging from 3 to 12 months, starting with low doses and titrating upward. Dosing adjustments and reevaluation of therapies should be performed during these time periods. The need for pharmacologic prophylactic therapy is often considered in patients with frequent and moderate-to-severe headaches and may be identified by patterns of abortive use. Patients who experience =2 migraines per week, attacks that last =48 hours, or attacks of severe intensity are candidates for prophylactic therapy. Other candidates may be patients who experience ineffective responses to abortive medications, who have contraindications to abortive therapies, or who experience attacks that follow a pattern, as in MM.36-40 The USHC recommends that preventive therapy be considered when a patient requires reduction in headache frequency or severity because the headaches interfere with activities of daily living despite abortive management.33,40 Table 5 lists commonly used preventive prescription therapies for migraine therapy. Data on the available nutritional and herbal therapies, including riboflavin, fish oil supplements, and herbals such as feverfew, are limited.36-42
When choosing an abortive therapy for the treatment of an acute migraine attack, a number of factors are considered, including delivery method, associated symptoms, desired outcomes, acceptance of therapy, cost, and patient perceptions.43-50 Migraine patients may experience gastric stasis during their attacks along with nausea and vomiting, which may prohibit the use of oral agents and require concurrent promotility drugs, eg, metoclopramide and/or injectable, rectal, or inhaled prescription therapies. Other considerations include contraindications and comorbidities, such as avoiding the ergot derivatives and triptans in patients with significant cardiac or cerebral vascular disease.37-41,49,50 Because the majority of migraine patients do not consult physicians for an evaluation of their migraines, the pharmacist is often in a first-line position when confronted by a patient for advice on the use of OTC analgesics for migraine treatment.51 This can be a challenging clinical decision and requires an adequate understanding of headaches. The first step is to ask the appropriate questions about the patient's medical and headache history (Table 6). If the pharmacist is not entirely clear as to the possible causes, a referral is recommended.7,49
FDA-approved OTC analgesics used in the management of migraine include Anacin (aspirin/caffeine), Advil Migraine (ibuprofen), and Excedrin Migraine (acetaminophen/aspirin/caffeine, or AAC). The simple analgesics include acetaminophen (APAP) (Note: APAP has not been approved for thetreatment of migraine), salicylates (both acetylated, ie, aspirin [ASA], and the nonacetylated), as well as combinations of ASA and APAP with additional ingredients including caffeine, ie, AAC, and OTC nonsteroidal anti-inflammatory drugs (NSAIDs).11
Clinical Studies with OTC Analgesics
Limited clinical data support the role of APAP as monotherapy in the acute management of migraine, although some patients may obtain some benefit.40 The mode of action of APAP is probably through a central mechanism related to central prostaglandin inhibition.9,11,16 One controlled trial with APAP 1000 mg in migraine patients without significant disability or gastrointestinal symptoms reported benefits versus placebo.52 A few small comparison trials with NSAIDs, in adults and pediatric migraine patients, reported greater benefits with the NSAIDs versus APAP.53,54 Benefits in these trials were reported as improvements in headache pain and functional disability.52-54 Based on these studies, it may be warranted to recommend APAP to a patient diagnosed with a new-onset mild migraine not associated with significant disability such as bed rest or gastrointestinal symptoms. It should be noted, however, that APAP has not been approved by the FDA for the treatment of migraine.
Aspirin (ASA) may benefit some migraine patients through its anti-inflammatory mechanism similar to the other NSAIDs.37,41,55 Clinical trials conducted with aspirin in patients with mild-tosevere migraine in doses ranging from 900 to 1000 mg reported benefits versus placebo.55-60 Studies comparing 1000 mg of aspirin with other migraine abortives, including sumatriptan 50 mg and ibuprofen 400 mg, reported similar efficacy, but greater pain-free effects were found with sumatriptan at 2 hours.58,59 Many of these studies used formulations not available in the United States, including effervescent products. Benefits in these trials were reported as improvements in headache pain intensity, pain-free response, recurrence, and other symptoms of migraine including nausea.56-59 Based on these trials, the role of aspirin in the treatment of migraine is not clear. Side effects of aspirin and other salicylates are described elsewhere and include gastrointestinal problems and tinnitus, especially at high doses.37,41 Because the dosage forms in the majority of studies are not available in the United States, aspirin should not be considered a firstline therapy in mild-to-moderate migraine.
The simple analgesics APAP and ASA in combination with caffeine have been studied in the abortive treatment of migraine. This combination (AAC) was the first OTC product approved by the FDA for the treatment of migraine. Caffeine is added to the simple analgesics to enhance their gastrointestinal absorption and to potentiate their activity.11,37,39,43,44 Clinical trials using this combination in the abortive treatment of patients with mild-to-moderate migraine reported significant benefits versus placebo61-63 and similar or greater efficacy versus other abortive therapies studied, namely, ibuprofen and sumatriptan.64,65 The doses used in these trials were 2 tablets of the combination of APAP 250 mg, ASA 250 mg, and caffeine 65 mg. These trials reported siginificant benefits in onset of pain relief, reduction of pain intensity, sustained response, and reduction of migraine-associated symptoms of nausea, vomiting, and sensory features. In the AAC-versus-sumatriptan study, the authors suggested that additional larger trials are needed to confirm their results.65 These studies demonstrated that the AAC is an effective FDA-approved agent in patients with mild-to-moderate migraine attacks. One of the most common side effects associated with the AAC combination in these trials was transient stomach discomfort/dyspepsia, with an incidence of about 2% to 9%. This was probably attributable to the ASA component. Nervousness and dizziness, which occurred in about 3% to 4% of patients, were probably attributable to the caffeine component. Compared with ibuprofen and sumatriptan, the AAC combination was similarly well-tolerated in head-to-head trials.64,65 Nervousness occurred slightly more frequently with the AAC combination than with ibuprofen (1.9% vs 0.3%).64 The proportion of patients reporting side effects under the broad category of gastrointestinal complaints was most common with the AAC combination (21.7% vs 7.5% in the sumatriptan group).65
NSAIDs have been reported to be effective in the abortive therapy of mild-to-moderate migraine.66-77 These agents function similarly to ASA through their inhibition of prostaglandins, which may interfere with the neurogenic inflammation associated with vasoactive peptide release during migraine.37,41 The majority of clinical studies using OTC available doses (Table 4) have been conducted with ibuprofen, and data with naproxen sodium is with prescription formulations at higher doses.66-77 Controlled trials in doses ranging from 200 to 1200 mg of ibuprofen reported increased benefits versus placebo. Results reported improvements in pain response, intensity, pain-free status, and the sensory and gastrointestinal symptoms of migraine.66-68 Comparison trials with other abortives, including aspirin and zolmitriptan in adults and pediatric patients, reported similar efficacy, although more gastrointestinal disturbances were found with ibuprofen.69-71 The side-effect profiles, contraindications, and drug interactions of the NSAIDs are well-documented elsewhere. Gastrointestinal side effects may present a concern in migraine patients with nausea and vomiting associated with their attacks. Although the importance of these parameters should not be taken lightly, and monitoring is required, they are usually not a major concern in the young migraine population. The role of the OTC NSAIDs in the management of migraine may be in patients with infrequent mild-to-moderate attacks who experience minimal gastrointestinal symptoms.11,37,41
Medication Overuse Headache
The consequences of overusing analgesics in the acute management of migraine can result in MOH and, over time, may actually interfere with appropriate headache pharmacotherapy. The mechanism of MOH is not completely clear but is thought to be related to alterations in serotonergic transmission.40 MOH is best described as overuse of analgesics resulting in chronic daily headaches.78,79 This unrecognized epidemic may involve millions of patients in the United States alone.79,80 The problem occurs primarily with prescription analgesics including opiate and barbiturate combination products (Table 3) but can occur with triptans and OTC analgesics.79,81,82 MOH is difficult to diagnose, and management may require abstinence periods to observe for reduced headaches, tapering of analgesics, and the use of other abortives or preventive medications.83-85 What constitutes excessive analgesic use for developing MOH is somewhat controversial and may vary from patient to patient. Usually, overuse of analgesics is defined as =3 daily doses of an abortive taken more than 2 to 3 days per week for extended periods of time or using analgesics more than 1 to 2 times weekly.83,86 The best treatment for MOH is prevention, and pharmacists are in a position to monitor analgesics usage, especially prescription therapy and OTC usage. Monitoring usage of OTC analgesics when counseling migraine patients is a great place to start. In some cases of MOH, inpatient headache treatment centers may be required to assist in the tapering and withdrawal of the analgesics, using a variety of medication treatment protocols.18,78,87-92
Although the focus of this article is OTC products, if a pharmacist notes the overuse of prescription analgesics in the monitoring of a patient's refill records,79-81 a call to the patient's physician or a discussion of overuse with the patient may be appropriate. When dispensing prescription analgesics, the importance of the education of patients cannot be overemphasized, instructing them to restrict their use of these products to <2 to 3 days per week and not for extended periods of time. If they continue these agents on a chronic basis, further evaluation and consideration of alternative abortive or prophylactic pharmacotherapy is indicated. In general, a patient who is experiencing 3 or more disabling migraine attacks per month should be evaluated for preventive therapy. Patients should become part of their evaluation and monitoring process by keeping diaries to evaluate effectiveness and frequency of use.93,94
Role of OTC Analgesics in the Acute Management of Migraine
Oral OTC analgesics have demonstrated benefits over placebo in the treatment of acute migraine attacks and several agents have been approved by the FDA. The challenge that the practicing pharmacist has is that it is not exactly clear from the studies what type of patients deserve a trial of an OTC agent for their migraine, or if they should be referred immediately to their primary care physician or a headache specialist.40 In addition, like other analgesics and triptans, the use of OTC agents in migraine management, if not used appropriately, may increase the potential for MOH.78,95
The methods of implementing initial abortive pharmacotherapy have been reviewed and studied by neurologists who are experts in the field of head pain and include the stepped-care and the stratified-care approaches. In the steppedcare approach, patients are treated with first-line drugs initially (eg, simple analgesics or combination analgesics), followed by triptans if the response is not satisfactory. The stratified approach on the other hand categorizes patients into various groups based on migraine history, severity, and disability and uses questionnaires to help stratify patients. The treatment choice is then based on where they are stratified. The Disability in Strategies of Care (DISC) study, a trial designed to evaluate these 2 approaches using the Migraine Disability Assessment Scale (MIDAS) questionnaire, reported greater benefits and cost-effectiveness with the stratified-care approach.96 The MIDAS scoring suggests the use of simple or combination analgesics in mild-tomoderate migraine, although in the DISC study these patients also received metoclopramide.96 Other guidelines have also been published and suggest similar recommendations for pharmacologic management.97-101
When the pharmacist is approached by a migraine patient for advice on OTC analgesic therapy, it is important to obtain an initial medical and headache history through questioning. Table 6 provides suggestions for questioning and obtaining this headache history.49 Abortive therapy with FDA-approved OTC analgesics may be appropriate in patients with a known diagnosis of migraine who experience mild-to-moderate attacks 2 to 4 times a year or <1 or 2 attacks per month. It is important that these patients have no contraindications to their use and understand the risk of overusing analgesic agents.93-98 Patients should also be reminded that, if headache intensity or frequency increases and the migraine fails to respond to OTC agents on a consistent basis, further evaluation is necessary. The decision as to which OTC analgesic to recommend in the migraine patient with mild-to-moderate headache may be based on the patient's previous response to OTC therapy or intolerance to a previous therapy. If a patient decides to use an OTC analgesic for his or her migraines and asks the pharmacist for advice, combination analgesic or OTC NSAIDs may be good first-line agents in mild-to-moderate migraine patients, due to their reported efficacy in clinical trials. Although side effects and toxicity of OTC NSAIDs are well-documented, these agents are usually well-tolerated in the young migraine patient. If aspirin is recommended, a higher dose is usually necessary (Table 4), and not all patients will tolerate these doses. If the patient has an allergy or history of gastrointestinal problems with NSAIDs, an alternative choice might include APAP alone or in a combination analgesic. If the combination product AAC is recommended, remind patients that this product contains as much caffeine as a cup of coffee and that they should limit the use of caffeine-containing medications, foods, or beverages while taking this product, because too much caffeine may cause nervousness, irritability, sleeplessness, and, occasionally, rapid heartbeat.11
When a product is chosen, instruct the patient to try the chosen therapy on 2 or 3 headaches and to take it the earliest signs of migraine onset. Always remind patients to evaluate their response to a given therapy and document the result in a headache diary. Examples of headache diaries can be viewed at the National Headache Foundation Web site at www.headaches.org under Educational Resources and Headache Diaries. The importance of educating patients on restricting their analgesic use cannot be overemphasized. If patients are using OTC or prescription analgesics >2 days each week on a regular basis, it may be time for further evaluation to avoid the risk of developing MOH.91,93 Any patient who presents with new-onset severe headaches that do not fit the clinical features of migraine or has no clear diagnosis of migraine should be referred for further evaluation.39,40,49,96-100
The Use of OTC Analgesics in Special Populations
The use of OTC analgesics in special populations poses unique challenges, and it is in the pharmacist's best interest to refer any new-onset headache in pediatric or geriatric patients to the primary care physician. The prevalence of migraine headache in children is 3% to 7% and increases in frequency as children reach the adolescent years. Any child with recurrent headaches should have a complete medical evaluation prior to the initiation of pharmacotherapy.102 As discussed earlier, 2 studies found ibuprofen and APAP to be effective and well-tolerated as first-line therapy for migraine in children.54,69-71 A practice parameter published in 2004 provides guidelines for the pharmacologic management of migraine in children and adolescents.103
Although the prevalence of headache declines with age, new-onset persistent headaches in the elderly may represent systemic or intracranial lesions or other serious disorders. Numerous disorders can manifest as headache in the elderly, and head pain needs prompt evaluation and follow-up.104,105 The diagnosis of headache in older adults, in particular migraine, is challenging due to a higher incidence of atypical presentation (eg, without aura or with aura alone). When migraine is diagnosed in an elderly patient, the presence of comorbidity and/or complex drug regimens can make treatment challenging. Other challenges in the management of elderly migraine patients include a history of cardiac disease or gastrointestinal bleeding risk, which are contraindications to the selective serotonin 5-HT receptor agonists (triptans) and the NSAIDs, respectively.106,107
Many female patients experience migraines in association with their menstrual cycle, allowing them to predict onset and duration. This may especially be the case if they are experiencing pure MM, described as migraine with aura that occurs exclusively during the menstrual period. Although NSAIDs have been studied in MM, the majority of data involves high doses of naproxen and other prescription therapies.15,108 Pharmacists may consider offering a trial of AAC or ibuprofen for use in the MM patient if a definitive diagnosis has been made and the cyclic features are evident from the patient. It is important to note that the data on dosing and use of ibuprofen are limited in this migraine type.15-17 Evidence for the efficacy of other OTC analgesics in MM includes the data from a post-hoc analysis discussed earlier with the combination analgesic, AAC.63
Treatment of migraine headaches during pregnancy is a difficult challenge, especially during the first trimester, when the fetus is at greatest risk from exposure to teratogenic drugs. A pregnant patient with migraine should be referred to the obstetrician for potential treatment options.109
George DeMaagd, PharmD, BCPS, is an Associate Professor of Pharmacy Practice, Ferris State University, College of Pharmacy, Mattawan, Mich.
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One study linked multiple pregnancies to an increased risk of developing atrial fibrillation later in life, and another investigated the association between premature delivery and cardiovascular disease.
Clinical features with downloadable PDFs