Neurol Sci (2014) 35 (Suppl 1):S61–S64 DOI 10.1007/s10072-014-1744-2
SESSION II MIGRAINE IN WOMEN
Migraine in pregnancy and lactation E. Anne MacGregor
Ó Springer-Verlag Italia 2014
Abstract Migraine in pregnancy can cause considerable concern to both patient and doctor, particularly if migraine starts for the first time during pregnancy or if the woman has her first attack with aura. There is often confusion regarding which medicines are safe to use during pregnancy and breastfeeding, leaving many women unable to control their attacks effectively. This paper reviews the diagnosis as well as the management of migraine, which is similar to the non-pregnant state, with a few exceptions. Keywords
Migraine Pregnancy Lactation
Introduction Migraine affects around 18 % of women, particularly during the reproductive years. Most women are able to control the symptoms of migraine with medication, using prophylactic drugs in addition, if attacks are frequent. When a woman is planning pregnancy, the potential effects of drugs on the fetus need to be considered, with careful review of all medication taken. Advice on safe and effective treatment of migraine during pregnancy is important as drugs have their greatest effects on the fetus during the first trimester, often before the woman knows she is pregnant. Medication needs further review if a woman is E. A. MacGregor (&) Barts Sexual Health Centre, St Bartholomew’s Hospital, London EC1A 7BE, UK e-mail: [email protected] E. A. MacGregor Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, UK
breastfeeding, due to the potential transfer of drugs in breast milk.
The effect of pregnancy and breastfeeding on migraine Up to 60–70 % of women with preexisting migraine report improvement or cessation of migraine during pregnancy, particularly in women with a history of menstrual migraine [1]. If no improvement is seen toward the end of the first trimester, migraine is likely to continue throughout pregnancy and postpartum [2]. Aura can occur for the first time during pregnancy and requires careful assessment if the symptoms are atypical [3, 4]. In such cases, thrombocytopenia, cerebral venous sinus thrombosis or imminent eclampsia should be excluded. Migraine following delivery is not uncommon, typically occurring a couple of days postpartum [2, 5, 6]. In women who bottle-feed, migraine tends to persist postpartum, whereas women who breastfeed maintain the protective effect of pregnancy until menstruation returns [2].
Effect of migraine on pregnancy Women can be reassured that there is no evidence that migraine has any significant adverse effect on the outcome of pregnancy [7, 8]. However, a number of studies have reported two to threefold increased risk of preeclampsia in pregnant migraineurs [9, 10]. Obesity was an additional risk factor carrying a 12-fold increased risk of preeclampsia in migraineurs compared with non-obese women without migraine. There is also evidence that migraine is a risk factor for pregnancy-related stroke [11]. Additional research needs to identify which type of migraine affects this risk.
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Table 1 Drugs used for acute treatment of migraine during pregnancy FDA category B
Table 2 Drugs for acute treatment of migraine during breastfeeding
Minimal risk Acetaminophen Diclofenac
Acetaminophen Diclofenac
3rd trimester: category D
Ibuprofen Cyclizine
Ibuprofen
3rd trimester: category D
Metoclopramide
Naproxen
3rd trimester: category D
Prochlorperazine
Meperidine
Category D if prolonged use/high doses at term
Promethazine Sumatriptan
Metoclopramide FDA category C
Benefits likely to outweigh risks Indometacin
Aspirin
3rd trimester: category D
Indomethacin
3rd trimester: category D
Mefenamic acid
3rd trimester: category D
Naproxen Codeine Morphine
Codeine
Meperidine
Morphine
Tramadol
Tramadol
Eletriptan
Prochlorperazine
Caution
Promethazine
Aspirin Mefenamic acid
Almotriptan Eletriptan
Contraindicated
Frovatriptan
Ergotamine
Naratriptan
Dihydroergotamine
Rizatriptan
Insufficient data
Sumatriptan Zolmitriptan
Almotriptan Frovatriptan
Prednisolone
Naratriptan
FDA category X
Rizatriptan
Ergotamine
Zolmitriptan
Dihydroergotamine
Acute treatment Investigations The indications for investigation of the pregnant women with headache are the same as for a non-pregnant woman. X-ray exposure should be avoided in favor of MRI, which is considered safe in pregnancy [12]. Contrast imaging with gadolinium can be undertaken, if indicated. Iodinated contrast media should be avoided as it can depress fetal thyroid function, which should be checked during the first week of birth.
Management Trigger management, particularly encouraging regular meals, regular exercise, sleep hygiene and adequate fluids may help reduce the frequency of attacks without the need for medication.
123
Most drugs are not licensed for use in pregnancy and during breastfeeding and should only be considered if the potential benefits to the woman and fetus outweigh the potential risks. The options for drug treatment are shown in Tables 1 and 2. Acetaminophen is the analgesic of choice for the shortterm relief of mild to moderate pain during pregnancy and lactation. Ibuprofen can be taken during the first and second trimesters but should be avoided after 30 weeks of pregnancy because of increased risk of premature closure of the ductus arteriosus and oligohydramnios. NSAIDs can be taken during breastfeeding, and the amount of drug in breast milk is very low. Aspirin can be taken during the first and second trimesters but use in the third trimester is associated with premature closure of the fetal ductus arteriosus and can increase the risk prolonged labor, post partum hemorrhage and neonatal bleeding. Aspirin is
Neurol Sci (2014) 35 (Suppl 1):S61–S64 Table 3 Drugs used for prophylaxis of migraine during pregnancy
FDA category C Amitriptyline Citalopram Escitalopram Fluoxetine Sertraline Venlafaxine Metoprolol Nadolol Propranolol Timolol Gabapentin Botulinum toxin FDA category D Atenolol Topiramate
S63
excreted in breast milk and regular use during breastfeeding can increase the risk Reye’s syndrome and impaired platelet function in susceptible infants. Antiemetics such as metoclopramide, prochlorperazine and promethazine can be taken during pregnancy and lactation. Sumatriptan may be used during pregnancy and breastfeeding if attacks fail to respond to the above treatment. Data from the sumatriptan/naratriptan/Treximet pregnancy registry (http://pregnancyregistry.gsk.com/sumatriptan. html) are reassuring and confirm that inadvertent exposure to sumatriptan during pregnancy has not been associated with adverse outcomes although a small increased risk of specific birth defects cannot be excluded. There are insufficient data regarding other triptans. Prophylaxis
Candesartan Lisinopril FDA category X Valproic acid
Table 4 Drugs used for prophylaxis of migraine during breastfeeding
Minimal risk Amitriptyline Nortriptyline Propranolol Verapamil Nifedipine Benefits likely to outweigh risks Metoprolol Escitalopram Paroxetine Sertraline Venlafaxine Gabapentin
Non-pharmacologic preventives such as acupuncture and biofeedback are useful during pregnancy [13, 14]. Coenzyme Q10 and magnesium supplements have the additional effect of reducing the risk of preeclampsia [15, 16]. The options for drug prophylaxis are shown in Tables 3 and 4. The drugs of choice during pregnancy and lactation are propranolol or metoprolol in the lowest effective doses. These should be stopped 2–3 days before delivery to minimize the risk fetal bradycardia and decreased uterine contraction. The baby should be monitored for neonatal bradycardia, hypotension and hypoglycemia. Low-dose amitriptyline 10–25 mg daily can also be taken during pregnancy and lactation. Although limb deformities have been reported following high-dose amitriptyline during pregnancy, there are no reports following doses of 10–50 mg daily used for pain management. Ideally, the dose is tapered 3–4 weeks before delivery to minimize neonatal drowsiness, jitteriness, hyperexcitability and suckling problems.
Topiramate Valproic acid
Emergency treatment
Concern Citalopram Fluoxetine Atenolol Nadolol Timolol Contraindicated
Prochlorperazine 10 mg or chlorpromazine 25–50 mg by intramuscular injection together with intravenous fluids is usually sufficient to abort an attack. Intravenous magnesium sulfate 1 g given over 15 min is an alternative and can be given together with intravenous prochlorperazine 10 mg [17].
Lithium Insufficient data Candesartan Lisinopril Botulinum toxin
Conclusions Women with a history of menstrual migraine often report improvement of migraine during pregnancy, which is
123
S64
sustained with breastfeeding. Migraine with aura is less likely to improve and may occur for the first time during pregnancy. Investigation of headache is the same as for the non-pregnant women, although routine investigations should be deferred until postpartum. First-line acute treatment during pregnancy and breastfeeding is with non-opioid analgesics and antiemetics. Sumatriptan may be indicated for severe attacks that do not respond to first-line treatment. If prophylaxis is indicated during pregnancy or lactation, the lowest effective dose of propranolol or amitriptyline are options. Conflict of interest Professor MacGregor has acted as a paid consultant to Bayer Healthcare, the Menarini Group, and Merck & Co, Inc.
References 1. Granella F, Sances G, Pucci E, Nappi RE, Ghiotto N et al (2000) Migraine with aura and reproductive life events: a case control study. Cephalalgia 20:701–707 2. Sances G, Granella F, Nappi RE, Fignon A, Ghiotto N et al (2003) Course of migraine during pregnancy and postpartum: a prospective study. Cephalalgia 23:197–205 3. Chancellor AM, Wroe SJ, Cull RE (1990) Migraine occurring for the first time in pregnancy. Headache 30:224–227 4. Cupini LM, Matteis M, Troisi E, Calabresi P, Bernardi G et al (1995) Sex-hormone-related events in migrainous females. A clinical comparative study between migraine with aura and migraine without aura. Cephalalgia 15:140–144 5. Kvisvik EV, Stovner LJ, Helde G, Bovim G, Linde M (2011) Headache and migraine during pregnancy and puerperium: the MIGRA-study. J Headache Pain 12:443–451
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Neurol Sci (2014) 35 (Suppl 1):S61–S64 6. Goldszmidt E, Kern R, Chaput A, Macarthur A (2005) The incidence and etiology of postpartum headaches: a prospective cohort study. Can J Anaesth 52:971–977 7. Wainscott G, Sullivan M, Volans G, Wilkinson M (1978) The outcome of pregnancy in women suffering from migraine. Postgrad Med 54:98–102 8. Banhidy F, Acs N, Horvath-Puho E, Czeizel AE (2007) Pregnancy complications and delivery outcomes in pregnant women with severe migraine. Eur J Obstet Gynecol Reprod Biol 134:157–163 9. Rotton WN, Sachtleben MR, Friedman EA (1959) Migraine and eclampsia. Obstet Gynecol 14:322–330 10. Adeney KL, Williams MA, Miller RS, Frederick IO, Sorensen TK et al (2005) Risk of preeclampsia in relation to maternal history of migraine headaches. J Matern Fetal Neonatal Med 18:167–172 11. James AH, Bushnell CD, Jamison MG, Myers ER (2005) Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol 106:509–516 12. ACOG (2004) ACOG Committee Opinion #299: guidelines for diagnostic imaging during pregnancy. Obstet Gynecol 104:647 13. Marcus DA, Scharff L, Turk DC (1995) Nonpharmacological management of headaches during pregnancy. Psychosom Med 57:527–535 14. Neri I, Allais G, Schiapparelli P, Blasi I, Benedetto C et al (2005) Acupuncture versus pharmacological approach to reduce hyperemesis gravidarum discomfort. Minerva Ginecol 57:471–475 15. Sandor PS, Di Clemente L, Coppola G, Saenger U, Fumal A et al (2005) Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Neurology 64:713–715 ´ fra J, Frese A, Goadsby PJ, Lind M et al (2009) EFNS 16. Evers S, A guideline on the drug treatment of migraine––revised report of an EFNS task force. Eur J Neurol 16:968–981 17. Demirkaya S, Vural O, Dora B, Topcuoglu MA (2001) Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks. Headache 41:171–177
SESSION II MIGRAINE IN WOMEN
Migraine in pregnancy and lactation E. Anne MacGregor
Ó Springer-Verlag Italia 2014
Abstract Migraine in pregnancy can cause considerable concern to both patient and doctor, particularly if migraine starts for the first time during pregnancy or if the woman has her first attack with aura. There is often confusion regarding which medicines are safe to use during pregnancy and breastfeeding, leaving many women unable to control their attacks effectively. This paper reviews the diagnosis as well as the management of migraine, which is similar to the non-pregnant state, with a few exceptions. Keywords
Migraine Pregnancy Lactation
Introduction Migraine affects around 18 % of women, particularly during the reproductive years. Most women are able to control the symptoms of migraine with medication, using prophylactic drugs in addition, if attacks are frequent. When a woman is planning pregnancy, the potential effects of drugs on the fetus need to be considered, with careful review of all medication taken. Advice on safe and effective treatment of migraine during pregnancy is important as drugs have their greatest effects on the fetus during the first trimester, often before the woman knows she is pregnant. Medication needs further review if a woman is E. A. MacGregor (&) Barts Sexual Health Centre, St Bartholomew’s Hospital, London EC1A 7BE, UK e-mail: [email protected] E. A. MacGregor Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, UK
breastfeeding, due to the potential transfer of drugs in breast milk.
The effect of pregnancy and breastfeeding on migraine Up to 60–70 % of women with preexisting migraine report improvement or cessation of migraine during pregnancy, particularly in women with a history of menstrual migraine [1]. If no improvement is seen toward the end of the first trimester, migraine is likely to continue throughout pregnancy and postpartum [2]. Aura can occur for the first time during pregnancy and requires careful assessment if the symptoms are atypical [3, 4]. In such cases, thrombocytopenia, cerebral venous sinus thrombosis or imminent eclampsia should be excluded. Migraine following delivery is not uncommon, typically occurring a couple of days postpartum [2, 5, 6]. In women who bottle-feed, migraine tends to persist postpartum, whereas women who breastfeed maintain the protective effect of pregnancy until menstruation returns [2].
Effect of migraine on pregnancy Women can be reassured that there is no evidence that migraine has any significant adverse effect on the outcome of pregnancy [7, 8]. However, a number of studies have reported two to threefold increased risk of preeclampsia in pregnant migraineurs [9, 10]. Obesity was an additional risk factor carrying a 12-fold increased risk of preeclampsia in migraineurs compared with non-obese women without migraine. There is also evidence that migraine is a risk factor for pregnancy-related stroke [11]. Additional research needs to identify which type of migraine affects this risk.
123
S62
Neurol Sci (2014) 35 (Suppl 1):S61–S64
Table 1 Drugs used for acute treatment of migraine during pregnancy FDA category B
Table 2 Drugs for acute treatment of migraine during breastfeeding
Minimal risk Acetaminophen Diclofenac
Acetaminophen Diclofenac
3rd trimester: category D
Ibuprofen Cyclizine
Ibuprofen
3rd trimester: category D
Metoclopramide
Naproxen
3rd trimester: category D
Prochlorperazine
Meperidine
Category D if prolonged use/high doses at term
Promethazine Sumatriptan
Metoclopramide FDA category C
Benefits likely to outweigh risks Indometacin
Aspirin
3rd trimester: category D
Indomethacin
3rd trimester: category D
Mefenamic acid
3rd trimester: category D
Naproxen Codeine Morphine
Codeine
Meperidine
Morphine
Tramadol
Tramadol
Eletriptan
Prochlorperazine
Caution
Promethazine
Aspirin Mefenamic acid
Almotriptan Eletriptan
Contraindicated
Frovatriptan
Ergotamine
Naratriptan
Dihydroergotamine
Rizatriptan
Insufficient data
Sumatriptan Zolmitriptan
Almotriptan Frovatriptan
Prednisolone
Naratriptan
FDA category X
Rizatriptan
Ergotamine
Zolmitriptan
Dihydroergotamine
Acute treatment Investigations The indications for investigation of the pregnant women with headache are the same as for a non-pregnant woman. X-ray exposure should be avoided in favor of MRI, which is considered safe in pregnancy [12]. Contrast imaging with gadolinium can be undertaken, if indicated. Iodinated contrast media should be avoided as it can depress fetal thyroid function, which should be checked during the first week of birth.
Management Trigger management, particularly encouraging regular meals, regular exercise, sleep hygiene and adequate fluids may help reduce the frequency of attacks without the need for medication.
123
Most drugs are not licensed for use in pregnancy and during breastfeeding and should only be considered if the potential benefits to the woman and fetus outweigh the potential risks. The options for drug treatment are shown in Tables 1 and 2. Acetaminophen is the analgesic of choice for the shortterm relief of mild to moderate pain during pregnancy and lactation. Ibuprofen can be taken during the first and second trimesters but should be avoided after 30 weeks of pregnancy because of increased risk of premature closure of the ductus arteriosus and oligohydramnios. NSAIDs can be taken during breastfeeding, and the amount of drug in breast milk is very low. Aspirin can be taken during the first and second trimesters but use in the third trimester is associated with premature closure of the fetal ductus arteriosus and can increase the risk prolonged labor, post partum hemorrhage and neonatal bleeding. Aspirin is
Neurol Sci (2014) 35 (Suppl 1):S61–S64 Table 3 Drugs used for prophylaxis of migraine during pregnancy
FDA category C Amitriptyline Citalopram Escitalopram Fluoxetine Sertraline Venlafaxine Metoprolol Nadolol Propranolol Timolol Gabapentin Botulinum toxin FDA category D Atenolol Topiramate
S63
excreted in breast milk and regular use during breastfeeding can increase the risk Reye’s syndrome and impaired platelet function in susceptible infants. Antiemetics such as metoclopramide, prochlorperazine and promethazine can be taken during pregnancy and lactation. Sumatriptan may be used during pregnancy and breastfeeding if attacks fail to respond to the above treatment. Data from the sumatriptan/naratriptan/Treximet pregnancy registry (http://pregnancyregistry.gsk.com/sumatriptan. html) are reassuring and confirm that inadvertent exposure to sumatriptan during pregnancy has not been associated with adverse outcomes although a small increased risk of specific birth defects cannot be excluded. There are insufficient data regarding other triptans. Prophylaxis
Candesartan Lisinopril FDA category X Valproic acid
Table 4 Drugs used for prophylaxis of migraine during breastfeeding
Minimal risk Amitriptyline Nortriptyline Propranolol Verapamil Nifedipine Benefits likely to outweigh risks Metoprolol Escitalopram Paroxetine Sertraline Venlafaxine Gabapentin
Non-pharmacologic preventives such as acupuncture and biofeedback are useful during pregnancy [13, 14]. Coenzyme Q10 and magnesium supplements have the additional effect of reducing the risk of preeclampsia [15, 16]. The options for drug prophylaxis are shown in Tables 3 and 4. The drugs of choice during pregnancy and lactation are propranolol or metoprolol in the lowest effective doses. These should be stopped 2–3 days before delivery to minimize the risk fetal bradycardia and decreased uterine contraction. The baby should be monitored for neonatal bradycardia, hypotension and hypoglycemia. Low-dose amitriptyline 10–25 mg daily can also be taken during pregnancy and lactation. Although limb deformities have been reported following high-dose amitriptyline during pregnancy, there are no reports following doses of 10–50 mg daily used for pain management. Ideally, the dose is tapered 3–4 weeks before delivery to minimize neonatal drowsiness, jitteriness, hyperexcitability and suckling problems.
Topiramate Valproic acid
Emergency treatment
Concern Citalopram Fluoxetine Atenolol Nadolol Timolol Contraindicated
Prochlorperazine 10 mg or chlorpromazine 25–50 mg by intramuscular injection together with intravenous fluids is usually sufficient to abort an attack. Intravenous magnesium sulfate 1 g given over 15 min is an alternative and can be given together with intravenous prochlorperazine 10 mg [17].
Lithium Insufficient data Candesartan Lisinopril Botulinum toxin
Conclusions Women with a history of menstrual migraine often report improvement of migraine during pregnancy, which is
123
S64
sustained with breastfeeding. Migraine with aura is less likely to improve and may occur for the first time during pregnancy. Investigation of headache is the same as for the non-pregnant women, although routine investigations should be deferred until postpartum. First-line acute treatment during pregnancy and breastfeeding is with non-opioid analgesics and antiemetics. Sumatriptan may be indicated for severe attacks that do not respond to first-line treatment. If prophylaxis is indicated during pregnancy or lactation, the lowest effective dose of propranolol or amitriptyline are options. Conflict of interest Professor MacGregor has acted as a paid consultant to Bayer Healthcare, the Menarini Group, and Merck & Co, Inc.
References 1. Granella F, Sances G, Pucci E, Nappi RE, Ghiotto N et al (2000) Migraine with aura and reproductive life events: a case control study. Cephalalgia 20:701–707 2. Sances G, Granella F, Nappi RE, Fignon A, Ghiotto N et al (2003) Course of migraine during pregnancy and postpartum: a prospective study. Cephalalgia 23:197–205 3. Chancellor AM, Wroe SJ, Cull RE (1990) Migraine occurring for the first time in pregnancy. Headache 30:224–227 4. Cupini LM, Matteis M, Troisi E, Calabresi P, Bernardi G et al (1995) Sex-hormone-related events in migrainous females. A clinical comparative study between migraine with aura and migraine without aura. Cephalalgia 15:140–144 5. Kvisvik EV, Stovner LJ, Helde G, Bovim G, Linde M (2011) Headache and migraine during pregnancy and puerperium: the MIGRA-study. J Headache Pain 12:443–451
123
Neurol Sci (2014) 35 (Suppl 1):S61–S64 6. Goldszmidt E, Kern R, Chaput A, Macarthur A (2005) The incidence and etiology of postpartum headaches: a prospective cohort study. Can J Anaesth 52:971–977 7. Wainscott G, Sullivan M, Volans G, Wilkinson M (1978) The outcome of pregnancy in women suffering from migraine. Postgrad Med 54:98–102 8. Banhidy F, Acs N, Horvath-Puho E, Czeizel AE (2007) Pregnancy complications and delivery outcomes in pregnant women with severe migraine. Eur J Obstet Gynecol Reprod Biol 134:157–163 9. Rotton WN, Sachtleben MR, Friedman EA (1959) Migraine and eclampsia. Obstet Gynecol 14:322–330 10. Adeney KL, Williams MA, Miller RS, Frederick IO, Sorensen TK et al (2005) Risk of preeclampsia in relation to maternal history of migraine headaches. J Matern Fetal Neonatal Med 18:167–172 11. James AH, Bushnell CD, Jamison MG, Myers ER (2005) Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol 106:509–516 12. ACOG (2004) ACOG Committee Opinion #299: guidelines for diagnostic imaging during pregnancy. Obstet Gynecol 104:647 13. Marcus DA, Scharff L, Turk DC (1995) Nonpharmacological management of headaches during pregnancy. Psychosom Med 57:527–535 14. Neri I, Allais G, Schiapparelli P, Blasi I, Benedetto C et al (2005) Acupuncture versus pharmacological approach to reduce hyperemesis gravidarum discomfort. Minerva Ginecol 57:471–475 15. Sandor PS, Di Clemente L, Coppola G, Saenger U, Fumal A et al (2005) Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Neurology 64:713–715 ´ fra J, Frese A, Goadsby PJ, Lind M et al (2009) EFNS 16. Evers S, A guideline on the drug treatment of migraine––revised report of an EFNS task force. Eur J Neurol 16:968–981 17. Demirkaya S, Vural O, Dora B, Topcuoglu MA (2001) Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks. Headache 41:171–177
