Curr Neurol Neurosci Rep (2014) 14:439 DOI 10.1007/s11910-014-0439-7
HEADACHE (R HALKER, SECTION EDITOR)
Migraine in Pregnancy and Lactation Paru S. David & Juliana M. Kling & Amaal J. Starling
Published online: 7 March 2014 # Springer Science+Business Media New York 2014
Abstract Migraine headache is a significant health problem affecting women more than men. In women, the hormonal fluctuations seen during pregnancy and lactation can affect migraine frequency and magnitude. Understanding the evaluation of headache in pregnancy is important, especially given the increased risk of secondary headache conditions. Pregnancy and lactation can complicate treatment options for women with migraine because of the risk of certain medications to the fetus. This review includes details of the workup and then provides treatment options for migraine during pregnancy and lactation.
pregnancy, lactation, and menopause affect many women’s migraines [2]. At the time of menarche, there is a steep rise in the prevalence of migraine, with a 3:1 female-to-male ratio [3]. The prevalence of migraine in women continues to rise during the reproductive years, reaching a peak of 24.4 %, followed by a decline around menopause [2–4]. The hormonal milieu specific to pregnancy and lactation plays an important role in migraine. This review explores this relationship as well as the recommended evaluation of migraine during pregnancy and lactation and ends with a summary of treatment options available during this time period.
Keywords Migraine . Headache . Pregnancy . Postpartum . Lactation . Treatment . Breastfeeding . Analgesics
Epidemiology of Migraine in Pregnancy and Lactation Effects of Pregnancy on Migraine
Introduction Migraine disproportionately affects women, with a lifetime prevalence of 22 % compared with 10 % in men [1]. Hormonal fluctuations that occur with menarche, menstruation, This article is part of the Topical Collection on Headache P. S. David (*) Division of Women’s Health-Internal Medicine, Department of Internal Medicine, Mayo Clinic, 13737 N. 92nd St, Scottsdale, AZ 85260, USA e-mail: [email protected] J. M. Kling Department of Internal Medicine, Mayo Clinic, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA e-mail: [email protected] A. J. Starling Division of Headache, Department of Neurology, Mayo Clinic, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA e-mail: [email protected]
Most women find improvement in migraine during their pregnancy. This finding is supported by several retrospective studies and small prospective trials, but until recently, large prospective trials have been lacking [3, 5–8]. In 2012, the MIGRA study, a large, prospective trial, reviewed headache and migraine during pregnancy and puerperium [9••]. Over 2,000 pregnant women with headache participated, with 208 fulfilling International Headache Society criteria for a diagnosis of migraine. Participants completed detailed headache diaries during pregnancy and puerperium. The study revealed a significant decrease in the frequency of migraine during pregnancy, specifically during the second and third trimesters irrespective of parity [9••]. Another study showed that 46.8 % of women with migraine found improvement in the first trimester, 83.0 % in the second trimester, and 87.2 % in the third trimester [8]. This improvement was mainly seen in patients who experienced migraine without aura prior to gestation. Only 43.6 % of women had improvement or remission of migraine with aura, compared with 76.8 % in women with
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migraine without aura [3]. A small percentage of women (3– 6 %) experience their first migraine during pregnancy [9••, 10]. In this context, the migraine usually occurs during the first trimester and is most often migraine with aura [11]. Postpartum Period and Effects of Lactation on Migraine Even though women experience improvement in migraine during pregnancy, most will experience recurrence shortly after delivery likely secondary to the precipitous drop in estradiol levels that occurs in the postpartum period. In a small prospective trial, migraine occurred in 4 % of women within 2 days of delivery, in 34 % of women by the first week, and in 55 % of women in the first month [8]. The MIGRA study confirmed that there is a sharp rise in the incidence of migraine in the first week and first month after delivery, but showed a decline in migraine frequency starting at 5 weeks after delivery [9••]. Breastfeeding had a protective effect and is associated with a lower recurrence rate than bottle feeding [8]. A recent study from Japan looked at the percentage of women experiencing migraine at 1, 3, 6, and 12 months after delivery, seeing if there was a difference in breastfeeding versus bottle feeding [12•]. In the breastfeeding group, the rates were 50 %, 65.8 %, 71.1 %, and 91.7 % respectively, whereas in the bottle feeding group, the rates were 86.4 %, 90.9 %, 95.5 %, and 81.3 % respectively, confirming that breastfeeding was associated with a reduced migraine recurrence [12•]. Breastfeeding should be encouraged in all women with a history of migraine. Migraine has no affect on the ability to lactate. Effects of Migraine on Pregnancy A personal history of migraine headaches can affect pregnancy outcomes. There is increasing evidence showing a link between migraine and vascular disorders during pregnancy, including gestational hypertension and preeclampsia [13]. Gestational hypertension is the development of new hypertension in a pregnant woman after 20 weeks’ gestation without proteinuria, whereas preeclampsia is new hypertension plus proteinuria. Migraine and preeclampsia share common pathways with regard to enhanced clotting, platelet activation, and vascular function [13]. Retrospective, case–control studies have demonstrated a strong association between migraine and preeclampsia [14, 15], and a recent prospective cohort study demonstrated that migrainous women had a higher risk of developing either gestational hypertension or preeclampsia [16]. Moreover, lack of remission of migraine during pregnancy is associated with these two hypertensive disorders in pregnancy [16]. There were similar rates of gestational hypertension in women experiencing migraine with aura and migraine without aura (11.1 % and 10.3 % respectively); however, there was a difference in the two groups for preeclampsia (5.9 % and 2.9 %, respectively) [16]. The association between
Curr Neurol Neurosci Rep (2014) 14:439
migraine and gestational hypertension and preeclampsia was confirmed in a large US population-based case–control study in 2009 [odds ratio (OR) 2.3; 95 % confidence interval (CI), 2.1–2.5] that looked at pregnancy-related hospital discharge codes [17]. Additionally, this study showed that peripartum migraine was strongly associated with ischemic stroke (OR 30.7; 95 % CI, 11.1–22.5), myocardial infarction (OR 4.9; 95 % CI, 1.7–14.2), deep vein thrombosis(OR 2.4; 95 % CI, 1.3–4.2), and thrombophilia (OR 3.6; 95 % CI, 2.1–6.1) [17]. Migraine should be considered a potential cardiovascular risk factor in obstetric care.
Evaluating Migraine During Pregnancy and Lactation The first step in the evaluation of headache is the differentiation of a primary headache disorder, such as migraine, from a secondary headache disorder. Pregnancy is a risk factor for a secondary headache disorder, thus making further evaluation for secondary causes of headache essential [18]. The secondary headache types influenced by pregnancy include benign intracranial hypertension, arteriovenous malformations, headaches of preeclampsia and eclampsia, brain tumors such as pituitary adenomas and meningiomas, hemorrhagic and thrombotic stroke, cerebral venous sinus thrombosis, and reversible cerebral vasoconstriction syndrome [18, 19]. Those that occur with increased frequency during pregnancy include cerebral venous thrombosis, acute strokes, symptomatic brain tumors, subarachnoid hemorrhage from ruptured arteriovenous malformations, and benign intracranial hypertension [20]. Additionally, certain conditions can mimic migraine during pregnancy and puerperium, including low-pressure headache related to spinal anesthesia, eclampsia/ preeclampsia, cerebral venous thrombosis, subarachnoid hemorrhage, intracranial tumors, idiopathic intracranial hypertension, and meningitis. Consideration of these diagnoses is imperative as they require additional evaluation and treatment. The most important part of the headache evaluation in pregnancy is a thorough history and physical examination, including fundoscopic examination, paying special attention to headache characteristics, medications, and past medical history, as well as looking for red flags. History components that are considered red flags include thunderclap or suddenonset headache, the worst headache of life, chronic unilateral headaches, headaches that wake a patient up at night, headaches with associated vision changes such as dimming vision or prolonged auras, and focal neurologic findings such as weakness and numbness. If needed, all imaging modalities may be used during pregnancy to evaluate the patient for the underlying cause of headache, as none pose a risk to the mother. With abdominal shielding, there is minimal risk of CT of the head to the fetus [18]. However, MRI is the preferred modality as it is considered to be safe to the mother and
Curr Neurol Neurosci Rep (2014) 14:439
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fetus [21]. Use of contrast agents such as gadolinium is discouraged because of lack of data regarding safety to the fetus [22]. Lumbar puncture can be performed without risk to either the mother or the fetus and should be done if there is concern for meningeal infection or subarachnoid hemorrhage. Moreover, spinal fluid examination findings such as cell count, opening pressure, and protein levels can be interpreted similarly in pregnant women as they are in nonpregnant patients, meaning abnormal findings should be investigated and not just attributed to pregnancy [23] Blood tests such as an autoimmune or coagulopathy workup should be considered on the basis of the history and physical examination [19].
Table 1 US Food and Drug Administration (FDA) category ratings for drugs used during pregnancy
Management of Migraine During Pregnancy and Lactation
D
Category Description A
Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the 1st trimester of pregnancy (and there is no evidence of risk in later trimesters)
B
Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but the potential benefits may warrant use of the drug in pregnant women despite the potential risks There is positive evidence of human fetal risk on the basis of adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits may warrant use of the drug in pregnant women despite the potential risks Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk on the basis of adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh the potential benefits
C
Nonpharmacologic Treatments X
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 [19]. Biofeedback and relaxation is safe and beneficial for pregnant and nursing women. Pregnant women who were treated with biofeedback had a 73 % reduction in their headaches compared with a 29 % reduction in the control group [24]. For 68 % of treated patients, the benefits lasted for up to 1 year postpartum [25]. Treatment of Migraine During Pregnancy The FDA has classified medications based on the available evidence of risk during pregnancy (Table 1). Category A is safe on the basis of controlled studies in humans, whereas categories D and X are contraindicated during pregnancy. Most medications fall in category C, where the risk to humans has not been ruled out on the basis of the available evidence. In the USA, no medications are in category A owing to the lack of controlled studies in pregnant women. For acute and preventative treatment of migraine in pregnancy, see Table 2. Acetaminophen (category B) and metoclopramide (category B) are recommended as first-line treatment for acute migraine attacks. NSAIDs, such as ibuprofen and naproxen, in the first and second trimesters (category B) can be used as well; however, in the third trimester NSAIDs are in category D because of renal development. Ondansetron (category B) can be used for migraine-associated nausea. Triptans (category C), 5-HT1B/5-HT1D agonists, are the mainstay of the acute treatment of migraine in the nonpregnant population. There are no human data to suggest teratogenicity [26, 27]. Only 15 % of the drug crosses the placenta; however, fetal 5-HT1B/5-HT1D receptors are present in the third trimester, and therefore, it is unclear if triptans can affect fetal health [26]. Pregnancy
registry data are inconsistent. The Norwegian Mother and Child Cohort Study, an observational, prospective population-based study of almost 70,000 pregnant women, demonstrated no significant association between triptan therapy and major congenital malformations or adverse pregnancy outcomes [28]. However, analysis of data from the Danish Medical Birth Registry found an association between preterm delivery and sumatriptan use [29]. Opioid and butalbitalcontaining medications (category B/C) should be used sparingly for the acute treatment of migraine. The treatment of status migrainosus in pregnancy has not been studied; however, at our institution nerve blocks with a local anesthetic and outpatient infusions are effective, tolerated, and safe. Occipital, supraorbital, or temporoauricular Table 2 Pharmacologic treatment of migraine during pregnancy FDA category Acute treatment of migraine during pregnancy Acetaminophen Metoclopramide NSAIDs during the 1st and 2nd trimesters Opioids and butalbital-containing medications Preventive treatment of migraine during pregnancy Magnesium Vitamin B2 (riboflavin) Coenzyme Q10
B B B/C B/C B C C
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nerve blocks can be used effectively with little or no risk to the fetus. Outpatient infusions include a cocktail of 1 L normal saline, 1 g magnesium, and 10 mg metoclopramide. Category D and X medications should not be used during pregnancy. Acute medications in these classes include NSAIDs in the third trimester, ergotamines, methysergide, ergot derivatives, and dihydroergotamine. Although the avoidance of a daily medication to prevent migraine attacks during pregnancy is ideal, if attacks occur twice a week or more, often despite nonpharmacologic treatments, prophylaxis is recommended [30]. Most preventive medications for migraine treatment fall into category C. Numerous vitamins, herbs, and supplements are used to effectively decrease the frequency of migraine headaches in nonpregnant women. These include butterbur, magnesium, riboflavin, feverfew, and coenzyme Q10 [31]. Per the European Federation of Neurological Societies, magnesium is the only supplement that can be used safely during pregnancy [32]. The effects of butterbur, riboflavin, and coenzyme Q10 during pregnancy are unknown and feverfew can prolong bleeding times, and therefore they are not recommended [18, 31, 33, 34]. Occipital, supraorbital, and temporoauricular nerve blocks can be used for prophylaxis as well. Preventive medications in categories D and X include divalproex sodium, carbamazepine, topiramate, and atenolol. These should not be used. Onabotulinum toxin a is not approved for use during pregnancy. Treatment of Migraine During Lactation During lactation, the dose of the drug that the infant receives is dependent on the average plasma concentration of the drug in
the mother and the amount secreted in the breast milk, which depends on lipophilicity and protein binding [35]. It is expressed quantitatively as a milk-to-plasma ratio. The cutoff marker for low risk to nursing infants is 10 % or less [36]. Decreased lipophilicity and increased protein binding decreases the dose of the drug in breast milk [35]. The National Library of Medicine’s Drugs and Lactation Database (LactMed) is an excellent, easily accessible, peerreviewed resource (http://toxnet.nlm.nih.gov/cgi-bin/sis/ htmlgen?LACT) [37]. LactMed does not give a rating or recommendation to medication, but rather lists the facts. However, three additional resources—from the American Academy of Pediatrics (AAP) [35], Medication in Mothers’ Milk by Hale [38], and Drugs in Pregnancy and Lactation by Briggs et al. [39]—do categorize the medications on the basis of risk. Hale [38] uses a scale from L1 to L5 (L1 safest, L2 safer, L3 moderately safe, L4 possibly hazardous, L5 contraindicated) . Briggs et al. [39] categorize the medications on the basis of the recommendation [compatible, hold breastfeeding; probably compatible, no (limited) human data; potential toxicity, no (limited) human data, or contraindicated]. These resources are the best reference for any medication recommended to a nursing mother. However, below we review some of the more commonly used migraine medications and their recommendations from the three abovementioned resources. For the acute treatment of migraine during lactation, see Table 3. Acetaminophen is considered safe by all three resources. NSAIDs, such as diclofenac and ibuprofen, are considered compatible with breastfeeding. Triptan medications for the acute treatment of migraine are considered safe during lactation, with minimal risk to infant. Although there is more safety evidence for sumatriptan, eletriptan is
Table 3 Pharmacologic treatment of migraine during lactation Medication Acute treatment of migraine during lactation Acetaminophen Ibuprofen Diclofenac Sumatriptan Eletriptan Preventive treatment of migraine during lactation Magnesium Vitamin B2 (riboflavin) Valproic acid Gabapentin Propranolol Verapamil Onabotulinum toxin A AAP American Academy of Pediatrics
AAP
Hale rating
Briggs et al. category
Compatible Compatible Not reviewed Compatible Not reviewed
L1 L1 L2 L3 L2
Compatible Compatible Probably compatible Probably compatible Compatible
Compatible Compatible Compatible Not reviewed Compatible Compatible Not reviewed
L1 L1 L2 L2 L2 L2 L3
Compatible Compatible Probably toxicity Probably compatible Probably toxicity Probably compatible Probably compatible
Curr Neurol Neurosci Rep (2014) 14:439
highly protein bound and i thought to be even safer owing to the lower doses present in breast milk. Only sumatriptan has been reviewed by the AAP, and is compatible with breastfeeding. However, eletriptan is considered the “safest” by Hale (L2) and Briggs et al. (compatible). Opiods and butalbital-containing medications can be used. Acute migraine medications that should be avoided or used with caution include aspirin, dihydroergotamine, ergotamine, opiods, and butalbital-containing medications. For the preventive treatment of migraine during lactation, see Table 3. As in preventive treatment during pregnancy, magnesium and riboflavin are safe during lactation. Antiepiletpic medications, antihypertensive medications, and tricyclic antidepressants remain the three first-line agents for migraine prophylaxis. Although other antiepileptic drugs should be avoided owing to high milk-to-plasma ratios, valproic acid was rated compatible by the AAP, on the basis of low milk levels. Gabapentin, although not yet reviewed by the AAP, is categorized as L2 by Hale and probably compatible by Briggs et al. Antihypertensives commonly used for migraine prophylaxis, such as propranolol and verapamil, are compatible with breastfeeding per the AAP. Tricyclic antidepressants have a very high milk-to-plasma ratio [40]. The AAP remains concerned about the effects of these medications on the nursing infant; thus, they should be avoided if possible. Onabotulinum toxin A is not secreted in breast milk if it is injected into muscle; however, it has not yet been reviewed by the AAP, and has been categorized by Hale as L3 and by Briggs et al. as probably compatible.
Conclusions Migraine disproportionately affects women, especially during the reproductive years. Although migraine improves for most pregnant women, there are a number of women who continue to experience migraine during pregnancy and into the postpartum period. For women who have a reduction in migraine during pregnancy, many have a resurgence of migraine the first year postpartum. A personal history of migraine headaches can affect pregnancy outcomes, and there is increasing evidence that shows a link between migraine and vascular disorders during pregnancy, including gestational hypertension and preeclampsia. Lack of remission of migraine during pregnancy is associated with these two hypertensive disorders in pregnancy. Pregnancy is a risk factor for a secondary headache disorder, thus making differentiation of a primary headache disorder, such as migraine, from a secondary headache disorder and further evaluation for secondary causes of headache essential. The data suggest that some women, with or without aura, continue to experience migraine attacks throughout pregnancy, and these women should be offered treatment. Not all
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medications used for migraine in nonpregnant women are considered safe in pregnancy. Similarly, some medications are considered safer than others during lactation, and knowing which medications to use during pregnancy and lactation is essential. Compliance with Ethics Guidelines Conflict of Interest Paru S. David, Juliana M. Kling, and Amaal J. Starling declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Stovner L et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27(3):193–210. 2. Nappi RE, Berga SL. Migraine and reproductive life. Handb Clin Neurol. 2010;97:303–22. 3. Granella F et al. Migraine with aura and reproductive life events: a case control study. Cephalalgia. 2000;20(8):701–7. 4. Lipton RB et al. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41(7):646–57. 5. Granella F et al. Migraine without aura and reproductive life events: a clinical epidemiological study in 1300 women. Headache. 1993;33(7):385–9. 6. Marcus DA, Scharff L, Turk D. Longitudinal prospective study of headache during pregnancy and postpartum. Headache. 1999;39(9):625–32. 7. Mattsson P. Hormonal factors in migraine: a population-based study of women aged 40 to 74 years. Headache. 2003;43(1):27–35. 8. Sances G et al. Course of migraine during pregnancy and postpartum: a prospective study. Cephalalgia. 2003;23(3):197–205. 9.•• Kvisvik EV et al. Headache and migraine during pregnancy and puerperium: the MIGRA-study. J Headache Pain. 2011;12(4):443– 51. This large, prospective trial confirms that most women have improvement in migraine during pregnancy, yet a number of women do have migraine that persists in pregnancy. Also, it demonstrates an increase in postpartum migraine after delivery in most women. 10. Melhado EM, Maciel Jr JA, Guerreiro CA. Headache during gestation: evaluation of 1101 women. Can J Neurol Sci. 2007;34(2): 187–92. 11. Nappi RE et al. Headaches during pregnancy. Curr Pain Headache Rep. 2011;15(4):289–94. 12.• Hoshiyama E et al. Postpartum migraines: a long-term prospective study. Intern Med. 2012;51(22):3119–23. This prospective study looks at migraine in the first year postpartum and shows that women who breastfeed have fewer migraines than women who bottle feed. 13. Allais G et al. The risks of women with migraine during pregnancy. Neurol Sci. 2010;31 Suppl 1:S59–61.
439, Page 6 of 6 14.
Facchinetti F et al. The relationship between headache and preeclampsia: a case-control study. Eur J Obstet Gynecol Reprod Biol. 2005;121(2):143–8. 15. Sanchez SE et al. Headaches and migraines are associated with an increased risk of preeclampsia in Peruvian women. Am J Hypertens. 2008;21(3):360–4. 16. Facchinetti F et al. Migraine is a risk factor for hypertensive disorders in pregnancy: a prospective cohort study. Cephalalgia. 2009;29(3):286–92. 17. Bushnell CD, Jamison M, James AH. Migraines during pregnancy linked to stroke and vascular diseases: US population based casecontrol study. BMJ. 2009;338:b664. 18. Digre KB. Headaches during pregnancy. Clin Obstet Gynecol. 2013;56(2):317–29. 19. Marcus DA. Managing headache during pregnancy and lactation. Expert Rev Neurother. 2008;8(3):385–95. 20. Marcus DA. Headache in pregnancy. Curr Pain Headache Rep. 2003;7(4):288–96. 21. Levine D, Barnes PD, Edelman RR. Obstetric MR imaging. Radiology. 1999;211(3):609–17. 22. Garcia-Bournissen F, Shrim A, Koren G. Safety of gadolinium during pregnancy. Can Fam. 2006;52:309–10. 23. Davis LE. Normal laboratory values of CSF during pregnancy. Arch Neurol. 1979;36(7):443. 24. Marcus DA, Scharff L, Turk DC. Nonpharmacological management of headaches during pregnancy. Psychosom Med. 1995;57(6):527–35. 25. Scharff L, Marcus DA, Turk DC. Maintenance of effects in the nonmedical treatment of headaches during pregnancy. Headache. 1996;36(5):285–90. 26. Loder E. Safety of sumatriptan in pregnancy: a review of the data so far. CNS Drugs. 2003;17(1):1–7.
Curr Neurol Neurosci Rep (2014) 14:439 27. 28.
29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40.
Soldin OP, Dahlin J, O'Mara DM. Triptans in pregnancy. Ther Drug Monit. 2008;30(1):5–9. Nezvalova-Henriksen K, Spigset O, Nordeng H. Triptan exposure during pregnancy and the risk of major congenital malformations and adverse pregnancy outcomes: results from the Norwegian Mother and Child Cohort Study. Headache. 2010;50(4):563–75. Olesen C et al. Pregnancy outcome following prescription for sumatriptan. Headache. 2000;40(1):20–4. Silberstein SD. Headaches in pregnancy. J Headache Pain. 2005;6(4):172–4. Rakel D. Integrative medicine. 3rd ed. Philadelphia: Saunders; 2012. Evers S et al. EFNS guideline on the drug treatment of migraine report of an EFNS task force. Eur J Neurol. 2006;13(6):560–72. Airola G et al. Non-pharmacological management of migraine during pregnancy. Neurol Sci. 2010;31 Suppl 1:S63–5. Menon R, Bushnell CD. Headache and pregnancy. Neurologist. 2008;14(2):108–19. Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108(3):776–89. Nice FJ, Luo AC. Medications and breast-feeding: current concepts. J Am Pharm Assoc. 2012;52(1):86–94. LactMed. National Library of Medicine, Bethesda. 2011. http:// toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT. Hale T. Medication and mothers' milk. 14th ed. Amarillo: Hale; 2010. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 9th ed. Philadelphia: Lippincott Wilkins and Williams; 2011. Atkinson HC, Begg EJ, Darlow BA. Drugs in human milk. Clinical pharmacokinetic considerations. Clin Pharmacokinet. 1988;14(4): 217–40.
HEADACHE (R HALKER, SECTION EDITOR)
Migraine in Pregnancy and Lactation Paru S. David & Juliana M. Kling & Amaal J. Starling
Published online: 7 March 2014 # Springer Science+Business Media New York 2014
Abstract Migraine headache is a significant health problem affecting women more than men. In women, the hormonal fluctuations seen during pregnancy and lactation can affect migraine frequency and magnitude. Understanding the evaluation of headache in pregnancy is important, especially given the increased risk of secondary headache conditions. Pregnancy and lactation can complicate treatment options for women with migraine because of the risk of certain medications to the fetus. This review includes details of the workup and then provides treatment options for migraine during pregnancy and lactation.
pregnancy, lactation, and menopause affect many women’s migraines [2]. At the time of menarche, there is a steep rise in the prevalence of migraine, with a 3:1 female-to-male ratio [3]. The prevalence of migraine in women continues to rise during the reproductive years, reaching a peak of 24.4 %, followed by a decline around menopause [2–4]. The hormonal milieu specific to pregnancy and lactation plays an important role in migraine. This review explores this relationship as well as the recommended evaluation of migraine during pregnancy and lactation and ends with a summary of treatment options available during this time period.
Keywords Migraine . Headache . Pregnancy . Postpartum . Lactation . Treatment . Breastfeeding . Analgesics
Epidemiology of Migraine in Pregnancy and Lactation Effects of Pregnancy on Migraine
Introduction Migraine disproportionately affects women, with a lifetime prevalence of 22 % compared with 10 % in men [1]. Hormonal fluctuations that occur with menarche, menstruation, This article is part of the Topical Collection on Headache P. S. David (*) Division of Women’s Health-Internal Medicine, Department of Internal Medicine, Mayo Clinic, 13737 N. 92nd St, Scottsdale, AZ 85260, USA e-mail: [email protected] J. M. Kling Department of Internal Medicine, Mayo Clinic, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA e-mail: [email protected] A. J. Starling Division of Headache, Department of Neurology, Mayo Clinic, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA e-mail: [email protected]
Most women find improvement in migraine during their pregnancy. This finding is supported by several retrospective studies and small prospective trials, but until recently, large prospective trials have been lacking [3, 5–8]. In 2012, the MIGRA study, a large, prospective trial, reviewed headache and migraine during pregnancy and puerperium [9••]. Over 2,000 pregnant women with headache participated, with 208 fulfilling International Headache Society criteria for a diagnosis of migraine. Participants completed detailed headache diaries during pregnancy and puerperium. The study revealed a significant decrease in the frequency of migraine during pregnancy, specifically during the second and third trimesters irrespective of parity [9••]. Another study showed that 46.8 % of women with migraine found improvement in the first trimester, 83.0 % in the second trimester, and 87.2 % in the third trimester [8]. This improvement was mainly seen in patients who experienced migraine without aura prior to gestation. Only 43.6 % of women had improvement or remission of migraine with aura, compared with 76.8 % in women with
439, Page 2 of 6
migraine without aura [3]. A small percentage of women (3– 6 %) experience their first migraine during pregnancy [9••, 10]. In this context, the migraine usually occurs during the first trimester and is most often migraine with aura [11]. Postpartum Period and Effects of Lactation on Migraine Even though women experience improvement in migraine during pregnancy, most will experience recurrence shortly after delivery likely secondary to the precipitous drop in estradiol levels that occurs in the postpartum period. In a small prospective trial, migraine occurred in 4 % of women within 2 days of delivery, in 34 % of women by the first week, and in 55 % of women in the first month [8]. The MIGRA study confirmed that there is a sharp rise in the incidence of migraine in the first week and first month after delivery, but showed a decline in migraine frequency starting at 5 weeks after delivery [9••]. Breastfeeding had a protective effect and is associated with a lower recurrence rate than bottle feeding [8]. A recent study from Japan looked at the percentage of women experiencing migraine at 1, 3, 6, and 12 months after delivery, seeing if there was a difference in breastfeeding versus bottle feeding [12•]. In the breastfeeding group, the rates were 50 %, 65.8 %, 71.1 %, and 91.7 % respectively, whereas in the bottle feeding group, the rates were 86.4 %, 90.9 %, 95.5 %, and 81.3 % respectively, confirming that breastfeeding was associated with a reduced migraine recurrence [12•]. Breastfeeding should be encouraged in all women with a history of migraine. Migraine has no affect on the ability to lactate. Effects of Migraine on Pregnancy A personal history of migraine headaches can affect pregnancy outcomes. There is increasing evidence showing a link between migraine and vascular disorders during pregnancy, including gestational hypertension and preeclampsia [13]. Gestational hypertension is the development of new hypertension in a pregnant woman after 20 weeks’ gestation without proteinuria, whereas preeclampsia is new hypertension plus proteinuria. Migraine and preeclampsia share common pathways with regard to enhanced clotting, platelet activation, and vascular function [13]. Retrospective, case–control studies have demonstrated a strong association between migraine and preeclampsia [14, 15], and a recent prospective cohort study demonstrated that migrainous women had a higher risk of developing either gestational hypertension or preeclampsia [16]. Moreover, lack of remission of migraine during pregnancy is associated with these two hypertensive disorders in pregnancy [16]. There were similar rates of gestational hypertension in women experiencing migraine with aura and migraine without aura (11.1 % and 10.3 % respectively); however, there was a difference in the two groups for preeclampsia (5.9 % and 2.9 %, respectively) [16]. The association between
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migraine and gestational hypertension and preeclampsia was confirmed in a large US population-based case–control study in 2009 [odds ratio (OR) 2.3; 95 % confidence interval (CI), 2.1–2.5] that looked at pregnancy-related hospital discharge codes [17]. Additionally, this study showed that peripartum migraine was strongly associated with ischemic stroke (OR 30.7; 95 % CI, 11.1–22.5), myocardial infarction (OR 4.9; 95 % CI, 1.7–14.2), deep vein thrombosis(OR 2.4; 95 % CI, 1.3–4.2), and thrombophilia (OR 3.6; 95 % CI, 2.1–6.1) [17]. Migraine should be considered a potential cardiovascular risk factor in obstetric care.
Evaluating Migraine During Pregnancy and Lactation The first step in the evaluation of headache is the differentiation of a primary headache disorder, such as migraine, from a secondary headache disorder. Pregnancy is a risk factor for a secondary headache disorder, thus making further evaluation for secondary causes of headache essential [18]. The secondary headache types influenced by pregnancy include benign intracranial hypertension, arteriovenous malformations, headaches of preeclampsia and eclampsia, brain tumors such as pituitary adenomas and meningiomas, hemorrhagic and thrombotic stroke, cerebral venous sinus thrombosis, and reversible cerebral vasoconstriction syndrome [18, 19]. Those that occur with increased frequency during pregnancy include cerebral venous thrombosis, acute strokes, symptomatic brain tumors, subarachnoid hemorrhage from ruptured arteriovenous malformations, and benign intracranial hypertension [20]. Additionally, certain conditions can mimic migraine during pregnancy and puerperium, including low-pressure headache related to spinal anesthesia, eclampsia/ preeclampsia, cerebral venous thrombosis, subarachnoid hemorrhage, intracranial tumors, idiopathic intracranial hypertension, and meningitis. Consideration of these diagnoses is imperative as they require additional evaluation and treatment. The most important part of the headache evaluation in pregnancy is a thorough history and physical examination, including fundoscopic examination, paying special attention to headache characteristics, medications, and past medical history, as well as looking for red flags. History components that are considered red flags include thunderclap or suddenonset headache, the worst headache of life, chronic unilateral headaches, headaches that wake a patient up at night, headaches with associated vision changes such as dimming vision or prolonged auras, and focal neurologic findings such as weakness and numbness. If needed, all imaging modalities may be used during pregnancy to evaluate the patient for the underlying cause of headache, as none pose a risk to the mother. With abdominal shielding, there is minimal risk of CT of the head to the fetus [18]. However, MRI is the preferred modality as it is considered to be safe to the mother and
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fetus [21]. Use of contrast agents such as gadolinium is discouraged because of lack of data regarding safety to the fetus [22]. Lumbar puncture can be performed without risk to either the mother or the fetus and should be done if there is concern for meningeal infection or subarachnoid hemorrhage. Moreover, spinal fluid examination findings such as cell count, opening pressure, and protein levels can be interpreted similarly in pregnant women as they are in nonpregnant patients, meaning abnormal findings should be investigated and not just attributed to pregnancy [23] Blood tests such as an autoimmune or coagulopathy workup should be considered on the basis of the history and physical examination [19].
Table 1 US Food and Drug Administration (FDA) category ratings for drugs used during pregnancy
Management of Migraine During Pregnancy and Lactation
D
Category Description A
Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the 1st trimester of pregnancy (and there is no evidence of risk in later trimesters)
B
Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but the potential benefits may warrant use of the drug in pregnant women despite the potential risks There is positive evidence of human fetal risk on the basis of adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits may warrant use of the drug in pregnant women despite the potential risks Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk on the basis of adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh the potential benefits
C
Nonpharmacologic Treatments X
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 [19]. Biofeedback and relaxation is safe and beneficial for pregnant and nursing women. Pregnant women who were treated with biofeedback had a 73 % reduction in their headaches compared with a 29 % reduction in the control group [24]. For 68 % of treated patients, the benefits lasted for up to 1 year postpartum [25]. Treatment of Migraine During Pregnancy The FDA has classified medications based on the available evidence of risk during pregnancy (Table 1). Category A is safe on the basis of controlled studies in humans, whereas categories D and X are contraindicated during pregnancy. Most medications fall in category C, where the risk to humans has not been ruled out on the basis of the available evidence. In the USA, no medications are in category A owing to the lack of controlled studies in pregnant women. For acute and preventative treatment of migraine in pregnancy, see Table 2. Acetaminophen (category B) and metoclopramide (category B) are recommended as first-line treatment for acute migraine attacks. NSAIDs, such as ibuprofen and naproxen, in the first and second trimesters (category B) can be used as well; however, in the third trimester NSAIDs are in category D because of renal development. Ondansetron (category B) can be used for migraine-associated nausea. Triptans (category C), 5-HT1B/5-HT1D agonists, are the mainstay of the acute treatment of migraine in the nonpregnant population. There are no human data to suggest teratogenicity [26, 27]. Only 15 % of the drug crosses the placenta; however, fetal 5-HT1B/5-HT1D receptors are present in the third trimester, and therefore, it is unclear if triptans can affect fetal health [26]. Pregnancy
registry data are inconsistent. The Norwegian Mother and Child Cohort Study, an observational, prospective population-based study of almost 70,000 pregnant women, demonstrated no significant association between triptan therapy and major congenital malformations or adverse pregnancy outcomes [28]. However, analysis of data from the Danish Medical Birth Registry found an association between preterm delivery and sumatriptan use [29]. Opioid and butalbitalcontaining medications (category B/C) should be used sparingly for the acute treatment of migraine. The treatment of status migrainosus in pregnancy has not been studied; however, at our institution nerve blocks with a local anesthetic and outpatient infusions are effective, tolerated, and safe. Occipital, supraorbital, or temporoauricular Table 2 Pharmacologic treatment of migraine during pregnancy FDA category Acute treatment of migraine during pregnancy Acetaminophen Metoclopramide NSAIDs during the 1st and 2nd trimesters Opioids and butalbital-containing medications Preventive treatment of migraine during pregnancy Magnesium Vitamin B2 (riboflavin) Coenzyme Q10
B B B/C B/C B C C
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nerve blocks can be used effectively with little or no risk to the fetus. Outpatient infusions include a cocktail of 1 L normal saline, 1 g magnesium, and 10 mg metoclopramide. Category D and X medications should not be used during pregnancy. Acute medications in these classes include NSAIDs in the third trimester, ergotamines, methysergide, ergot derivatives, and dihydroergotamine. Although the avoidance of a daily medication to prevent migraine attacks during pregnancy is ideal, if attacks occur twice a week or more, often despite nonpharmacologic treatments, prophylaxis is recommended [30]. Most preventive medications for migraine treatment fall into category C. Numerous vitamins, herbs, and supplements are used to effectively decrease the frequency of migraine headaches in nonpregnant women. These include butterbur, magnesium, riboflavin, feverfew, and coenzyme Q10 [31]. Per the European Federation of Neurological Societies, magnesium is the only supplement that can be used safely during pregnancy [32]. The effects of butterbur, riboflavin, and coenzyme Q10 during pregnancy are unknown and feverfew can prolong bleeding times, and therefore they are not recommended [18, 31, 33, 34]. Occipital, supraorbital, and temporoauricular nerve blocks can be used for prophylaxis as well. Preventive medications in categories D and X include divalproex sodium, carbamazepine, topiramate, and atenolol. These should not be used. Onabotulinum toxin a is not approved for use during pregnancy. Treatment of Migraine During Lactation During lactation, the dose of the drug that the infant receives is dependent on the average plasma concentration of the drug in
the mother and the amount secreted in the breast milk, which depends on lipophilicity and protein binding [35]. It is expressed quantitatively as a milk-to-plasma ratio. The cutoff marker for low risk to nursing infants is 10 % or less [36]. Decreased lipophilicity and increased protein binding decreases the dose of the drug in breast milk [35]. The National Library of Medicine’s Drugs and Lactation Database (LactMed) is an excellent, easily accessible, peerreviewed resource (http://toxnet.nlm.nih.gov/cgi-bin/sis/ htmlgen?LACT) [37]. LactMed does not give a rating or recommendation to medication, but rather lists the facts. However, three additional resources—from the American Academy of Pediatrics (AAP) [35], Medication in Mothers’ Milk by Hale [38], and Drugs in Pregnancy and Lactation by Briggs et al. [39]—do categorize the medications on the basis of risk. Hale [38] uses a scale from L1 to L5 (L1 safest, L2 safer, L3 moderately safe, L4 possibly hazardous, L5 contraindicated) . Briggs et al. [39] categorize the medications on the basis of the recommendation [compatible, hold breastfeeding; probably compatible, no (limited) human data; potential toxicity, no (limited) human data, or contraindicated]. These resources are the best reference for any medication recommended to a nursing mother. However, below we review some of the more commonly used migraine medications and their recommendations from the three abovementioned resources. For the acute treatment of migraine during lactation, see Table 3. Acetaminophen is considered safe by all three resources. NSAIDs, such as diclofenac and ibuprofen, are considered compatible with breastfeeding. Triptan medications for the acute treatment of migraine are considered safe during lactation, with minimal risk to infant. Although there is more safety evidence for sumatriptan, eletriptan is
Table 3 Pharmacologic treatment of migraine during lactation Medication Acute treatment of migraine during lactation Acetaminophen Ibuprofen Diclofenac Sumatriptan Eletriptan Preventive treatment of migraine during lactation Magnesium Vitamin B2 (riboflavin) Valproic acid Gabapentin Propranolol Verapamil Onabotulinum toxin A AAP American Academy of Pediatrics
AAP
Hale rating
Briggs et al. category
Compatible Compatible Not reviewed Compatible Not reviewed
L1 L1 L2 L3 L2
Compatible Compatible Probably compatible Probably compatible Compatible
Compatible Compatible Compatible Not reviewed Compatible Compatible Not reviewed
L1 L1 L2 L2 L2 L2 L3
Compatible Compatible Probably toxicity Probably compatible Probably toxicity Probably compatible Probably compatible
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highly protein bound and i thought to be even safer owing to the lower doses present in breast milk. Only sumatriptan has been reviewed by the AAP, and is compatible with breastfeeding. However, eletriptan is considered the “safest” by Hale (L2) and Briggs et al. (compatible). Opiods and butalbital-containing medications can be used. Acute migraine medications that should be avoided or used with caution include aspirin, dihydroergotamine, ergotamine, opiods, and butalbital-containing medications. For the preventive treatment of migraine during lactation, see Table 3. As in preventive treatment during pregnancy, magnesium and riboflavin are safe during lactation. Antiepiletpic medications, antihypertensive medications, and tricyclic antidepressants remain the three first-line agents for migraine prophylaxis. Although other antiepileptic drugs should be avoided owing to high milk-to-plasma ratios, valproic acid was rated compatible by the AAP, on the basis of low milk levels. Gabapentin, although not yet reviewed by the AAP, is categorized as L2 by Hale and probably compatible by Briggs et al. Antihypertensives commonly used for migraine prophylaxis, such as propranolol and verapamil, are compatible with breastfeeding per the AAP. Tricyclic antidepressants have a very high milk-to-plasma ratio [40]. The AAP remains concerned about the effects of these medications on the nursing infant; thus, they should be avoided if possible. Onabotulinum toxin A is not secreted in breast milk if it is injected into muscle; however, it has not yet been reviewed by the AAP, and has been categorized by Hale as L3 and by Briggs et al. as probably compatible.
Conclusions Migraine disproportionately affects women, especially during the reproductive years. Although migraine improves for most pregnant women, there are a number of women who continue to experience migraine during pregnancy and into the postpartum period. For women who have a reduction in migraine during pregnancy, many have a resurgence of migraine the first year postpartum. A personal history of migraine headaches can affect pregnancy outcomes, and there is increasing evidence that shows a link between migraine and vascular disorders during pregnancy, including gestational hypertension and preeclampsia. Lack of remission of migraine during pregnancy is associated with these two hypertensive disorders in pregnancy. Pregnancy is a risk factor for a secondary headache disorder, thus making differentiation of a primary headache disorder, such as migraine, from a secondary headache disorder and further evaluation for secondary causes of headache essential. The data suggest that some women, with or without aura, continue to experience migraine attacks throughout pregnancy, and these women should be offered treatment. Not all
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medications used for migraine in nonpregnant women are considered safe in pregnancy. Similarly, some medications are considered safer than others during lactation, and knowing which medications to use during pregnancy and lactation is essential. Compliance with Ethics Guidelines Conflict of Interest Paru S. David, Juliana M. Kling, and Amaal J. Starling declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Stovner L et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27(3):193–210. 2. Nappi RE, Berga SL. Migraine and reproductive life. Handb Clin Neurol. 2010;97:303–22. 3. Granella F et al. Migraine with aura and reproductive life events: a case control study. Cephalalgia. 2000;20(8):701–7. 4. Lipton RB et al. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41(7):646–57. 5. Granella F et al. Migraine without aura and reproductive life events: a clinical epidemiological study in 1300 women. Headache. 1993;33(7):385–9. 6. Marcus DA, Scharff L, Turk D. Longitudinal prospective study of headache during pregnancy and postpartum. Headache. 1999;39(9):625–32. 7. Mattsson P. Hormonal factors in migraine: a population-based study of women aged 40 to 74 years. Headache. 2003;43(1):27–35. 8. Sances G et al. Course of migraine during pregnancy and postpartum: a prospective study. Cephalalgia. 2003;23(3):197–205. 9.•• Kvisvik EV et al. Headache and migraine during pregnancy and puerperium: the MIGRA-study. J Headache Pain. 2011;12(4):443– 51. This large, prospective trial confirms that most women have improvement in migraine during pregnancy, yet a number of women do have migraine that persists in pregnancy. Also, it demonstrates an increase in postpartum migraine after delivery in most women. 10. Melhado EM, Maciel Jr JA, Guerreiro CA. Headache during gestation: evaluation of 1101 women. Can J Neurol Sci. 2007;34(2): 187–92. 11. Nappi RE et al. Headaches during pregnancy. Curr Pain Headache Rep. 2011;15(4):289–94. 12.• Hoshiyama E et al. Postpartum migraines: a long-term prospective study. Intern Med. 2012;51(22):3119–23. This prospective study looks at migraine in the first year postpartum and shows that women who breastfeed have fewer migraines than women who bottle feed. 13. Allais G et al. The risks of women with migraine during pregnancy. Neurol Sci. 2010;31 Suppl 1:S59–61.
439, Page 6 of 6 14.
Facchinetti F et al. The relationship between headache and preeclampsia: a case-control study. Eur J Obstet Gynecol Reprod Biol. 2005;121(2):143–8. 15. Sanchez SE et al. Headaches and migraines are associated with an increased risk of preeclampsia in Peruvian women. Am J Hypertens. 2008;21(3):360–4. 16. Facchinetti F et al. Migraine is a risk factor for hypertensive disorders in pregnancy: a prospective cohort study. Cephalalgia. 2009;29(3):286–92. 17. Bushnell CD, Jamison M, James AH. Migraines during pregnancy linked to stroke and vascular diseases: US population based casecontrol study. BMJ. 2009;338:b664. 18. Digre KB. Headaches during pregnancy. Clin Obstet Gynecol. 2013;56(2):317–29. 19. Marcus DA. Managing headache during pregnancy and lactation. Expert Rev Neurother. 2008;8(3):385–95. 20. Marcus DA. Headache in pregnancy. Curr Pain Headache Rep. 2003;7(4):288–96. 21. Levine D, Barnes PD, Edelman RR. Obstetric MR imaging. Radiology. 1999;211(3):609–17. 22. Garcia-Bournissen F, Shrim A, Koren G. Safety of gadolinium during pregnancy. Can Fam. 2006;52:309–10. 23. Davis LE. Normal laboratory values of CSF during pregnancy. Arch Neurol. 1979;36(7):443. 24. Marcus DA, Scharff L, Turk DC. Nonpharmacological management of headaches during pregnancy. Psychosom Med. 1995;57(6):527–35. 25. Scharff L, Marcus DA, Turk DC. Maintenance of effects in the nonmedical treatment of headaches during pregnancy. Headache. 1996;36(5):285–90. 26. Loder E. Safety of sumatriptan in pregnancy: a review of the data so far. CNS Drugs. 2003;17(1):1–7.
Curr Neurol Neurosci Rep (2014) 14:439 27. 28.
29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40.
Soldin OP, Dahlin J, O'Mara DM. Triptans in pregnancy. Ther Drug Monit. 2008;30(1):5–9. Nezvalova-Henriksen K, Spigset O, Nordeng H. Triptan exposure during pregnancy and the risk of major congenital malformations and adverse pregnancy outcomes: results from the Norwegian Mother and Child Cohort Study. Headache. 2010;50(4):563–75. Olesen C et al. Pregnancy outcome following prescription for sumatriptan. Headache. 2000;40(1):20–4. Silberstein SD. Headaches in pregnancy. J Headache Pain. 2005;6(4):172–4. Rakel D. Integrative medicine. 3rd ed. Philadelphia: Saunders; 2012. Evers S et al. EFNS guideline on the drug treatment of migraine report of an EFNS task force. Eur J Neurol. 2006;13(6):560–72. Airola G et al. Non-pharmacological management of migraine during pregnancy. Neurol Sci. 2010;31 Suppl 1:S63–5. Menon R, Bushnell CD. Headache and pregnancy. Neurologist. 2008;14(2):108–19. Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108(3):776–89. Nice FJ, Luo AC. Medications and breast-feeding: current concepts. J Am Pharm Assoc. 2012;52(1):86–94. LactMed. National Library of Medicine, Bethesda. 2011. http:// toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT. Hale T. Medication and mothers' milk. 14th ed. Amarillo: Hale; 2010. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 9th ed. Philadelphia: Lippincott Wilkins and Williams; 2011. Atkinson HC, Begg EJ, Darlow BA. Drugs in human milk. Clinical pharmacokinetic considerations. Clin Pharmacokinet. 1988;14(4): 217–40.
