Abstract
Migraine is common during pregnancy, but fortunately this combination of conditions obviously exists for only a finite period. The greatest frequency of migraine attacks occurs during the first trimester. Accurate diagnosis is a sine qua non in this setting as in any headache patient. It is in the first trimester that the fetus is at greatest risk from abortifacient and teratogenic drugs, and when very early pregnancy may be undiagnosed. Ergot alkaloids (including methysergide) should be avoided during pregnancy because of their teratogenicity, and most other drug classes should be used only when unavoidable. The use of prophylactic agents during pregnancy should be the exception, not the rule, and preferably only during the second and third trimesters; propranolol is probably safest in this situation. De novo headache during pregnancy usually requires expert review of the patient. Treatment tactics for uncomplicated migraine in pregnancy depend on the concurrent clinical situation. Paracetamol (acetaminophen) is the mainstay for the patient whose typical attacks continue into the first trimester. If paracetamol is insufficient, then partial agonist opioids may be used if typical migraine attacks persist in the second and third trimesters (which is uncommon). ‘Chronicmigraine’ in pregnancy, i.e. ≥15 headache days per month, is rare, and is the greatest therapeutic challenge. Co-morbidities such as depression or epilepsy require specialised approaches. The complexities associated with these tactics are discussed in this article, and it is emphasised that none has the specific approval of regulatory authorities. Heightened pharmacovigilance will better inform the future pregnant migraineur. However, this type of information is less likely to be available for novel classes of neuropharmacological agents than for existing ones.
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References
Stewart WF, Linet MS, Celentano DD, et al. Age- and sex-specific rates of migraine with and without visual aura. Am J Epidemiol 1991; 134: 1111–20
Scher AI, Stewart WF, Lipton RB. Migraine and headache: a meta-analytic approach. In: Crombie I, editor. Epidemiology of pain. Seattle (WA): IASP, 1999: 159–70
Stang P, Osterhaus J. Impact of migraine in the United States: data from the National Health Interview Survey. Headache 1993; 33: 29–35
Silberstein SD. Hormone-related headache. Med Clin North Am 2001; 85: 1017–35
Fox AW, Davis RL. Migraine chronobiology. Headache 1998; 38: 436–41
Marcus DA, Scharff L, Turk D. Longitudinal prospective study of headache during pregnancy and postpartum. Headache 1999; 39: 625–32
Sances G, Granella F, Nappi RE, et al. Course of migraine during pregnancy and postpartum. Cephalalgia 2003; 23: 197–205
Chen TC, Leviton A. Headache recurrence in pregnant women with migraine. Headache 1994; 34: 107–10
Granella F, Sances G, Pucci E, et al. Migraine with aura and reproductive life events: a case control study. Cephalalgia 2000; 20: 701–7
Olesen J, Bousser M-G, Diener HC, et al. The international classification of headache disorders. 2nd ed. Cephalalgia 2004; 24Suppl. 1: 1–160
Spierings ELH, Ranke AH, Honkoop PC. Precipitating and aggravating factors of migraine versus tension-type headache. Headache 2001; 41: 554–8
Diamond ML. Emergency room treatment of migraine headache. Curr Treat Options Neurol 2002; 4: 351–6
Diamond ML. Emergency department management of the acute headache. Clin Cornerstone 1999; 1: 45–54
Silberstein SD. Migraine and pregnancy. Neurol Clin 1997; 15: 209–31
Spierings ELH. Acute and chronic hypertensive headache and hypertensive encephalopathy. Cephalalgia 2002; 22: 313–6
Modi M, Modi G. Case reports: postpartum cerebral angiopathy in a patient with chronic migraine with aura. Headache 2000; 40: 677–81
Bending JJ. Recurrent bilateral reversible migrainous hemiparesis during pregnancy. CMAJ 1982; 127: 508–9
Jacobson SL, Redman CW. Basilar migraine with loss of consciousness in pregnancy. Case report. Br J Obstet Gynaecol 1989; 96: 494–5
Mandel S. Hemiplegic migraine in pregnancy. Headache 1988; 28: 414–6
Barbour PJ, Castaldo JE, Shoemaker EI. Hemiplegic migraine during pregnancy: unusual magnetic resonance appearance with SPECT scan correlation. Headache 2001; 41: 310–6
Marcoux S, Berube S, Brisson J, et al. History of migraine and risk of pregnancy-induced hypertension. Epidemiology 1992; 3: 53–6
Evans RW, Rothrock JF. Migraine aura without headache versus transient ischemic attack during pregnancy. Headache 2001; 41: 414–5
Passchier J, Kaminsky MM, Paarlberg KM, et al. Stress during pregnancy is unrelated to headache change in migraineurs [letter]. Headache 1996; 36: 189
Chancellor AM, Wroe SJ, Cull RE. Migraine occurring for the first time during pregnancy. Headache 1990; 30: 224–7
Uknis A, Silberstein SD. Review article: migraine and pregnancy. Headache 1991; 31: 372–4
Maggioni F, Alessi C, Maggino T, et al. Headache during pregnancy. Cephalalgia 1997; 17: 765–9
Tfelt-Hansen P. Drug treatment of migraine: acute treatment and migraine prophylaxis. Curr Opin Neurol 1996; 9: 211–3
Coppola M, Yealy DM, Leibold RA. Randomized, placebocontrolled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med 1995; 26: 541–6
Cameron JD, Lane PL, Speechley M. Intravenous chlorpromazine versus intravenous metoclopramide in acute migraine headache. Acad Emerg Med 1995; 2: 597–602
Sinha C, Ohadike P, Carrick P, et al. Neonatal outcome following maternal opiate use in late pregnancy. Int J Gynaecol Obstet 2001; 74: 241–46
Sharpe C, Kuschel C. Outcomes of infants born to mothers receiving methadone for pain management in pregnancy. Arch Dis Child Fetal Neonatal Ed 2004; 89: F33–6
McCarthy JE, Siney C, Shaw NJ, et al. Outcome predictors in pregnant opiate and polydrug users. Eur J Pediatr 1999; 158: 748–49
Malanga CJ, Kosofsky BE. Mechanisms of action of drugs of abuse on the developing fetal brain. Clin Perinatal 1999; 26: 17–37
Flint C, Larsen H, Nielsen GL, et al. Pregnancy outcome after suicide attempt by drug use: a Danish population-based study. Acta Obstet Gynecol Scand 2002; 81: 516–22
Vainio M, Kujansuu E, Iso-Mustajarvi M, et al. Low dose acetylsalicylic acid in prevention of pregnancy-induced hypertension and intrauterine growth retardation in women with bilateral uterine artery notches. Br J Obstet Gynaecol 2002; 109: 161–7
Remez L. Daily dose of aspirin in pregnancy appears to be ineffective in preventing or treating pre-eclampsia. Farn Plann Perspect 1994; 26: 239–40
Regan L, Rai R. Thrombophilia and pregnancy loss. J Reprod Immunol 2002; 55: 163–80
Rote NS. Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials [letter]. Obstet Gynecol 2002; 100: 173
Carmona F, Font J, Azulay M, et al. Risk factors associated with fetal losses in treated anti-phospholipid syndrome pregnancies: a multivariate analysis. Am J Reprod Immunol 2001; 46: 274–9
Lee RM, Silver RM. Recurrent pregnancy loss: summary and clinical recommendations. Semin Reprod Med 2000; 18: 433–40
Nomura T, Isa Y, Kurokawa N, et al. Enhancement effects of barbital on the teratogenicity of aminopyrine. Toxicology 1984; 29: 281–91
Alano MA, Ngougmna E, Ostrea EM, et al. Analysis of nonsteroidal anti-inflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics 2001; 107: 519–23
Morris JL, Rosen DA, Rosen KR. Nonsteroidal anti-inflammatory agents in neonates. Pediatr Drugs 2003; 5: 385–05
Silberstein SD, Saper J, Freitag FG. Migraine diagnosis and treatment. In: Silberstein SD, Lipton RB, Dalessio DJ, editors. Wolff’s headache and other head pain. 7th ed. Oxford: Oxford University Press, 2001: 157
Raja M, Altavista MC, Azzoni A, et al. Severe barbiturate withdrawal syndrome in a migrainous patient. Headache 1996; 36: 119–21
Blumenthal I, Lindsay S. Neonatal barbiturate withdrawal. Postgrad Med J 1977; 53: 157–8
Ostrea EM. Neonatal withdrawal from intrauterine exposure to butalbital. Am J Obstet Gynecol 1982; 143: 597–8
Dessens AB, Cohen-Kettenis PT, Mellenbergh GJ, et al. Association of prenatal phenobarbital and phenytoin exposure with genital anomalies and menstrual disorders. Teratology 2001; 64: 181–88
Holmes LB, Wyszynski DF, Liberman E. The AED (antiepileptic drug) pregnancy registry: a 6-year experience. Arch Neurol 2004; 61: 673–78
Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001; 344: 1132–38
Ching M. Effect of barbital on the pituitary-thyroid axis. J Endocrinol Invest 1981; 4: 389–92
McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol 1994; 8: 461–75
Erkkola R, Kero P, Kanto J, et al. Severe abuse of psychotropic drugs during pregnancy with good perinatal outcome. Ann Clin Res 1983; 15: 88–91
Mazzotta P, Magee LA. A risk-benefit assessment of pharmacological and non-pharmacological treatments for nausea and vomiting of pregnancy. Drugs 2000; 59: 781–800
Nehlig A, Debry G. Potential teratogenic and neurodevelopmental consequences of coffee and caffeine exposure: a review of human and animal data. Neurotoxicol Teratol 1994; 16: 531–43
Bracken MB, Triche EW, Belanger K, et al. Association of maternal caffeine consumption with decrements in fetal growth. Am J Epidemiol 2003; 157: 456–66
Diekman MA, Green ML. Mycotoxins and reproduction in domestic livestock. J Anim Sci 1992; 70: 1615–27
Baskett TF. A flux of the reds: evolution of active management of the third stage of labour. J R Soc Med 2000; 93: 489–93
Fox AW. Migraine therapy: seamlessness between plant-derived and synthetic drugs. J Herb Pharmacother 2002; 2: 3–18
Degroot ANJA, Van Dongen PWJ, Van Roosmalen J. Ergotamine-induced fetal distress: review of side-effects of ergot alkaloids during pregnancy. Eur J Obstet Gynecol Reprod Biol 1993; 51: 73–7
Graham JM, Marin-Padilla M, Hofnagel D. Jejunal atresia associated with Cafergot® ingestion during pregnancy. Clin Pediatr 1983; 22: 226–8
Hughes HE, Goldstein DA. Birth defects following maternal exposure to ergotamine, beta blockers and caffeine. J Med Genet 1988; 25: 396–9
Graf WD, Shepard TH. Uterine contraction in the development of Mobius syndrome. J Child Neurol 1997; 12: 225–7
Werler MM, Sheehan JE, Mitchell AA. Maternal medication use and risk of gastroschisis and small intestinal atresia. Am J Epidemiol 2002; 155: 26–31
Orioli IM, Castilla EE. Epidemiological assessment of misoprostol teratogenicity. Br J Obstet Gynecol 2000; 107: 519–23
Sayfan J. Ergotamine-induced anorectal strictures: report of five cases. Dis Colon Rectum 2002; 45(2): 271–2
Papalampros EL, Salakou SG, Felekouras ES, et al. Ischemic necrosis of gastric wall after long-term ergotamine pill abuse: case report and review of the literature. Dig Dis Sci 2001; 46: 981–4
Spierings ELH, Saxena PR. Pharmacology of arteriovenous anastomoses. Adv Neurol 1982; 33: 291–4
Spierings ELH, Saxena PR. Effect of isometheptene on the distribution and shunting of 15 micrometer microspheres throughout the cephalic circulation of the cat. Headache 1980; 20: 103–6
Diamond S. Treatment of migraine with isometheptene, acetaminophen and dichloralphenazone combination: a double-blind, crossover trial. Headache 1976; 15: 282–87
Freitag FG, Cady R, DiSerio F, et al. Comparative study of a combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the treatment of migraine. Headache 2001; 41: 391–98
Hardebo JE, Edvinsson L. Reduced sensitivity to alpha- and beta-adrenergic receptor agonists of intra- and extra-cranial vessels during pregnancy: relevance to migraine. Acta Neurol Scand Suppl 1977; 64: 204–5
Diamond S, Medina JL. Isometheptene-a non-ergot drug in the treatment of migraine. Headache 1975; 15: 211–13
Dodick DW, Martin V. Triptans and CNS side-effects: pharmacokinetic and metabolic mechanisms. Cephalalgia 2004; 24: 417–24
Schenker S, Yang Y, Perez A, et al. Sumatriptan (Imitrex®) transport by the human placenta. Proc Soc Exp Biol Med 1995; 210: 213–20
Loder E. Safety of sumatriptan in pregnancy: a review of the data so far. CNS Drugs 2003; 17(1): 1–7
Fox AW, Chambers CD, Anderson PO, et al. Evidence-based assessment of pregnancy outcome after sumatriptan exposure. Headache 2002; 42: 8–15
Evans RW, Diamond ML. Is sumatriptan use safe during pregnancy? Headache 2000; 40: 856–7
O’Quinn S, Ephross SA, William V, et al. Pregnancy and perinatal outcomes in migraineurs using sumatriptan: a prospective study. Arch Gynecol Obstet 1999; 263: 7–12
Olesen C, Steffensen FH, Sorensen HT, et al. Pregnancy outcome following prescription for sumatriptan. Headache 2000; 40: 20–4
Shuhaiber S, Pastuszak A, Schick B, et al. Pregnancy outcome following first trimester exposure to sumatriptan. Neurology 1998; 51: 581–3
Kallen B, Lygner PE. Delivery outcome in women who used drugs for migraine during pregnancy, with special reference to sumatriptan. Headache 2001; 41: 351–6
Reiff-Eldridge R, Heffner CR, Ephross SA, et al. Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment. Am J Obstet Gynecol 2000; 182: 159–63
Chambers CD, Johnson KA, Dick LM, et al. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996; 335: 1010–5
Putnam GP, O’Quinn S, Bolden-Watson CP, et al. Migraine polypharmacy and the tolerability of sumatriptan: a large-scale, prospective study. Cephalalgia 1999; 19: 668–75
Dowson AJ. Migraine: assessment and management. Int J Clin Pract 2001;55: 684–9
Spierings ELH. Migraine prevention and errors in living: Dr Graham’s lessons for patients and physicians. Headache 2002; 42: 152–3
Melchart D, Linde K, Fischer P, et al. Acupuncture for recurrent headaches: a systematic review of randomized controlled trials. Cephalalgia 1999; 19: 779–86
van der Kuy PH, Lohman JJ. A quantification of the placebo response in migraine prophylaxis. Cephalalgia 2002; 22: 265–70
Whitmarsh TE, Coleston-Shields DM, Steiner TJ. Double-blind randomized placebo-controlled study of homeopathic prophylaxis of migraine. Cephalalgia 1997; 17: 600–4
Fox AW. Complementary medicines. In: Fletcher AJ, Edwards LD, Fox AW, et al, editors. Principles and practice of pharmaceutical medicine. London: John Wiley and Sons, 2002: 281–6
Pfaffenrath V, Diener HC, Fischer M, et al. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis: a double-blind, multicentre, randomized, placebocontrolled dose-response study. Cephalalgia 2002; 22: 523–32
Murphy JJ, Heptinstall S, Mitchell JR. Randomised, double-blind, placebo-controlled trial of feverfew in migraine prevention. Lancet 1988; II: 189–92
Johnson ES, Kadam NP, Hylands DM, et al. Efficacy of feverfew as prophylactic treatment of migraine. BMJ (Clin Res) 1985; 291: 569–73
Grossmann M, Schmidramsl H. An extract of Petasites hybridus is effective in the prophylaxis of migraine. Int J Clin Pharmacol Ther 2000; 38: 430–5
Fox AW, de Sousa EAJ. “Herbal remedies” and patient protection. Headache 2001; 41: 323–6
Shahin M, Smith BL, Prakash AS. Bracken carcinogens in the human diet. Mutat Res 1999; 443: 69–79
Tomlinson B, Chan TYK, Chan JCN, et al. Toxicity of complementary therapies: an Eastern perspective. J Clin Pharmacol 2000; 40: 451–6
Nortier JL, Muniz Martinez MC, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aris-tolochia Fangchi). N Engl J Med 2000; 342: 1686–92
Henderson L, Yue QY, Bergquist C, et al. St. John’s Wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 2002; 54: 349–56
Mitchinson MJ. Methysergide and retroperitoneal fibrosis [letter]. Lancet 1987; I: 870
Limmroth V, Michel MC. The prevention of migraine: a critical review with special emphasis on beta-adrenoceptor blockers. Br J Clin Pharmacol 2001; 52: 237–43
Bernus I, Roberts MS, Rasiah RL, et al. Statistical moments for placental transfer of solutes in man. J Pharm Pharmacol 1999; 51: 1381–9
Smith MT, Livingstone I, Eadie MJ, et al. Metabolism of propranolol in the human maternal-placental-foetal unit. Eur J Clin Pharmacol 1983; 24: 727–32
Featherstone HJ. Fetal demise in a migraine patient on propranolol. Headache 1983; 23: 213–4
Chow T, Galvin J, McGovern B. Antiarrhythmic therapy in pregnancy and lactation. Am J Cardiol 1998; 82: 581–621
Paran E, Holzberg G, Mazor M, et al. Beta-adrenergic blocking agents in the treatment of pregnancy-induced hypertension. Int J Clin Pharmacol Ther 1995; 33: 119–23
Kleinman CS. Prenatal diagnosis and management of intrauterine arrhythmia. Fetal Ther 1986; 1: 92–5
Wagenvoort AM, van Vugt JM, Sobotka M, et al. Topical timolol therapy in pregnancy: is it safe for the fetus? Teratology 1998; 58: 258–62
Freitag FG, Collins SD, Carlson HA, et al. A randomized trial of divalproex sodium extended-release tablet in migraine prophylaxis. Neurology 2002; 58: 1652–9
Mathew NT. Antiepileptic drugs in migraine prevention. Headache 2001; 41Suppl. 1: S18–S24
Silberstein SD. Divalproex sodium in headache: literature review and clinical guidelines. Headache 1996; 36: 547–55
Adelman JU, Adelman LC, Von Seggern R. Cost-effectiveness of antiepileptic drugs in migraine prophylaxis. Headache 2002; 42: 978–83
Scott WJ, Schreiner CM, Nau H, et al. Valproate-induced limb malformations in mice associated with reduction in cellular pH. Reprod Toxicol 1997; 11: 483–93
Ernst CL, Goldberg JF. The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics. J Clin Psychiatry 2002; 63Suppl. 4: 42–55
Brandes JL, Saper JR, Diamond M, et al. Topiramate for migraine prevention. JAMA 2004; 291: 965–73
Palmieri C, Canger R. Teratogenic potential of the newer antiepileptic drugs: what is known and how should this influence prescribing? CNS Drugs 2002; 16: 755–64
Vahedi K, Taupin P, Djomby R, et al., for the DIAMIG Investigators. Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomized placebo-controlled trial. J Neurol 2002; 249: 206–11
Couch JR, Hassanein RS. Amitriptyline in migraine prophylaxis. Arch Neurol 1979; 36: 695–99
Wisner KL, Gelenberg AJ, Leonard H, et al. Pharmacologic treatment of depression during pregnancy. JAMA 1999; 282: 1264–9
Misri S, Kostaras D, Kostaras X. The use of selective serotonin reuptake inhibitors during pregnancy and lactation: current knowledge. Can J Psychiatry 2000; 45: 285–7
Diener HC, Matias-Guiu J, Hartung E, et al. Efficacy and tolerability in migraine prophylaxis of flunarizine reduced doses: a comparison with propranolol 160mg daily. Cephalalgia 2002; 22: 209–21
Spierings ELH. Calcium entry blockers in migraine: the state of the art. In: Hartmann A, Kushchinsky W, editors. Cerebral ischemia and calcium. Berlin & Heidelberg: Springer-Verlag, 1989: 391–97
Spierings ELH, Messinger HB. Flunarizine vs pizotifen in migraine prophylaxis: a review of comparative studies. Cephalalgia 1988; 8Suppl. 8: 27–30
Pfaffentrath V, Rehm M. Migraine in pregnancy: what are the safest treatment options? Drug Saf 1998; 19: 383–8
Rayburn WF, Lavin JP. Drug prescribing for chronic medical disorders during pregnancy: an overview. Am J Obstet Gynecol 1986; 155: 565–9
Silberstein SD. Headaches and women: treatment of the pregnant and lactating migraineur. Headache 1993; 33: 533–40
Miles CB. Treatment of migraine during pregnancy and lactation. S D J Med 1995; 48: 373–7
Paulson GW. Headaches in women, including women who are pregnant. Am J Obstet Gynecol 1995; 173: 1734–41
Rathmell JP, Viscomi CM, Ashburn MA. Management of non-obstetric pain during pregnancy and lactation. Anesth Analg 1997; 87: 1074–87
Marcus DA. Pregnancy and chronic headache. Exp Opin Pharmacother 2002; 3: 389–98
Hainline B. Migraine and other headache conditions. Adv Neurol 2002; 90: 25–40
Aube M. Migraine in pregnancy. Neurology 1999; 53Suppl. 1: S26–8
Fuller RW, Snoody HD. Inhibition of serotonin uptake and the toxic interaction between meperidine and monoamine oxidase inhibitors. Toxicol Appl Pharmacol 1975; 32: 129–34
Mathew NT, Reuveni U, Perez F. Transformed or evolutive migraine. Headache 1987; 27: 102-6
Acknowledgements
The authors are grateful to numerous colleagues for helpful discussions, over the years, on this clinical problem and kindred subjects. There was neither involvement of any pharmaceutical company in preparation of this manuscript nor any other external funding.
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Fox, A.W., Diamond, M.L. & Spierings, E.L.H. Migraine During Pregnancy. CNS Drugs 19, 465–481 (2005). https://doi.org/10.2165/00023210-200519060-00001
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DOI: https://doi.org/10.2165/00023210-200519060-00001