Management of primary headaches during pregnancy, postpartum, and breastfeeding: A systematic review
Corresponding Author
Ian J. Saldanha MBBS, MPH, PhD
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Correspondence
Ian J. Saldanha, Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Brown University School of Public Health, 121 S. Main Street, Box G-121-8, Providence, RI 02903, USA.
Email: [email protected]
Search for more papers by this authorWangnan Cao PhD
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorMonika Reddy Bhuma BDS, MPH
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorKristin J. Konnyu PhD
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorGaelen P. Adam MLIS, MPH
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorShivani Mehta BA
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorAndrew R. Zullo PharmD, PhD
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Center for Gerontology and Healthcare Research, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorKenneth K. Chen MD
Department of Medicine, Warren Alpert Medical School, Brown University, Providence, RI, USA
Department of Obstetrics and Gynecology, Warren Alpert Medical School, Brown University, Providence, RI, USA
Search for more papers by this authorJulie L. Roth MD
Department of Neurology, Brown University Warren Alpert Medical School, Providence, RI, USA
Search for more papers by this authorEthan M. Balk MD, MPH
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorCorresponding Author
Ian J. Saldanha MBBS, MPH, PhD
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Correspondence
Ian J. Saldanha, Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Brown University School of Public Health, 121 S. Main Street, Box G-121-8, Providence, RI 02903, USA.
Email: [email protected]
Search for more papers by this authorWangnan Cao PhD
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorMonika Reddy Bhuma BDS, MPH
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorKristin J. Konnyu PhD
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorGaelen P. Adam MLIS, MPH
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorShivani Mehta BA
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorAndrew R. Zullo PharmD, PhD
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Center for Gerontology and Healthcare Research, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorKenneth K. Chen MD
Department of Medicine, Warren Alpert Medical School, Brown University, Providence, RI, USA
Department of Obstetrics and Gynecology, Warren Alpert Medical School, Brown University, Providence, RI, USA
Search for more papers by this authorJulie L. Roth MD
Department of Neurology, Brown University Warren Alpert Medical School, Providence, RI, USA
Search for more papers by this authorEthan M. Balk MD, MPH
Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
Search for more papers by this authorAbstract
Background
Primary headaches (migraine, tension headache, cluster headache, and other trigeminal autonomic cephalgias) are common in pregnancy and postpartum. It is unclear how to best and most safely manage them.
Objective
We conducted a systematic review (SR) of interventions to prevent or treat primary headaches in women who are pregnant, attempting to become pregnant, postpartum, or breastfeeding.
Methods
We searched Medline, Embase, Cochrane CENTRAL, CINAHL, ClinicalTrials.gov, Cochrane Database of SRs, and Epistemonikos for primary studies of pregnant women with primary headache and existing SRs of harms in pregnant women regardless of indication. No date or language restrictions were applied. We assessed strength of evidence (SoE) using standard methods.
Results
We screened 8549 citations for studies and 2788 citations for SRs. Sixteen studies (mostly high risk of bias) comprising 14,185 patients (total) and 26 SRs met the criteria. For prevention, we found no evidence addressing effectiveness. Antiepileptics, venlafaxine, tricyclic antidepressants, benzodiazepines, β-blockers, prednisolone, and oral magnesium may be associated with fetal/child adverse effects, but calcium channel blockers and antihistamines may not be (1 single-group study and 11 SRs; low-to-moderate SoE). For treatment, combination metoclopramide and diphenhydramine may be more effective than codeine for migraine or tension headache (1 randomized controlled trial; low SoE). Triptans may not be associated with fetal/child adverse effects (8 nonrandomized comparative studies; low SoE). Acetaminophen, prednisolone, indomethacin, ondansetron, antipsychotics, and intravenous magnesium may be associated with fetal/child adverse effects, but low-dose aspirin may not be (indirect evidence; low-to-moderate SoE). We found insufficient evidence regarding non-pharmacologic treatments.
Conclusions
For prevention of primary headache, calcium channel blockers and antihistamines may not be associated with fetal/child adverse effects. For treatment, combination metoclopramide and diphenhydramine may be more effective than codeine. Triptans and low-dose aspirin may not be associated with fetal/child adverse effects. Future research should identify effective and safe interventions in pregnancy and postpartum.
CONFLICT OF INTEREST
The authors have no conflicts of interest to disclose.
REFERENCES
- 1Negro A, Delaruelle Z, Ivanova TA, et al. Headache and pregnancy: a systematic review. J Headache Pain. 2017; 18(1): 106.
- 2Ishii R, Schwedt TJ, Kim S-K, Dumkrieger G, Chong CD, Dodick DW. Effect of migraine on pregnancy planning: insights from the American Registry for Migraine Research. Mayo Clin Proc. 2020; 95(10): 2079-2089.
- 3Robbins MS, Farmakidis C, Dayal AK, Lipton RB. Acute headache diagnosis in pregnant women: a hospital-based study. Neurology. 2015; 85(12): 1024-1030.
- 4Andrade C. Valproate in pregnancy: recent research and regulatory responses. J Clin Psychiatry. 2018; 79(3):18f12351.
- 5Antonucci R, Zaffanello M, Puxeddu E, et al. Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn. Curr Drug Metab. 2012; 13(4): 474-490.
- 6Saldanha IJ, Roth JL, Chen KK, et al. Management of Primary Headaches in Pregnancy. Comparative Effectiveness Review No. 234. (Prepared by the Brown Evidence-based Practice Center under Contract No. 290-2015-00002-I.) AHRQ Publication No. 20(21)-EHC026. Rockville, MD: Agency for Healthcare Research and Quality (US); 2020. https://doi.org/10.23970/AHRQEPCCER234
10.23970/AHRQEPCCER234 Google Scholar
- 7 Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality (US); 2011. https://pubmed.ncbi.nlm.nih.gov/21433403/. Accessed August 8, 2020.
- 8Higgins JPT, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343:d5928.
- 9Sterne JAC, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016; 355:i4919.
- 10 National Heart, Lung, and Blood Institute. Study Quality Assessment Tools; 2019. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools. Accessed August 18, 2020.
- 11Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017; 358:j4008.
- 12Childress KMS, Dothager C, Gavard JA, Lebovitz S, Laska C, Mostello DJ. Metoclopramide and diphenhydramine: a randomized controlled trial of a treatment for headache in pregnancy when acetaminophen alone is ineffective (MAD headache study). Am J Perinatol. 2018; 35(13): 1281-1286.
- 13 Nct. A Cost Effective Treatment for Headache in Pregnancy When Acetaminophen Alone is Ineffective; 2014. https://clinicaltrialsgov/show/NCT02295280. Accessed August 18, 2020.
- 14Scolari Childress KM, Lebovitz SJ, Mostello DJ. Metoclopramide and diphenhydramine cost-effective therapy for headache in an obstetric triage unit. Obstet Gynecol. 2015; 125: 1S-2S.
- 15Silva JBGd, Nakamura MU, Cordeiro JA, Kulay L. Acupuncture for tension-type headache in pregnancy: a prospective, randomized, controlled study. Eur J Integr Med. 2012; 4(4): e366-e370.
- 16Marcus DA, Scharff L, Turk DC. Nonpharmacological management of headaches during pregnancy. Psychosom Med. 1995; 57(6): 527-535.
- 17Ephross SA, Sinclair SM. Final results from the 16-year sumatriptan, naratriptan, and treximet pregnancy registry. Headache. 2014; 54(7): 1158-1172.
- 18Cunnington M, Ephross S, Churchill P. The safety of sumatriptan and naratriptan in pregnancy: what have we learned? Headache. 2009; 49(10): 1414-1422.
- 19 Nct. Sumatriptan and Naratriptan Pregnancy Registry; 2014. https://ClinicalTrialsgov/show/NCT01059604. Accessed August 18, 2020.
- 20O'Quinn S, Ephross SA, Williams V, Davis RL, Gutterman DL, Fox AW. Pregnancy and perinatal outcomes in migraineurs using sumatriptan: a prospective study. Arch Gynecol Obstet. 1999; 263(1-2): 7-12.
- 21Shuhaiber S, Pastuszak A, Schick B, et al. Pregnancy outcome following first trimester exposure to sumatriptan. Neurology. 1998; 51(2): 581-583.
- 22Nezvalova-Henriksen K, Spigset O, Nordeng H. Triptan safety during pregnancy: a Norwegian population registry study. Eur J Epidemiol. 2013; 28(9): 759-769.
- 23Nezvalova-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): 563-575.
- 24Harris GE, Wood M, Ystrom E, Nordeng H. Prenatal triptan exposure and neurodevelopmental outcomes in 5-year-old children: follow-up from the Norwegian Mother and Child Cohort study. Paediatr Perinat Epidemiol. 2018; 32(3): 247-255.
- 25Nezvalova-Henriksen K, Spigset O, Nordeng HM. Errata in “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. 2012; 52(8): 1319-1320.
- 26Wood ME, Frazier JA, Nordeng HM, Lapane KL. Longitudinal changes in neurodevelopmental outcomes between 18 and 36 months in children with prenatal triptan exposure: findings from the Norwegian Mother and Child Cohort Study. BMJ Open. 2016; 6(9):e011971.
- 27Wood ME, Lapane K, Frazier JA, Ystrom E, Mick EO, Nordeng H. Prenatal triptan exposure and internalising and externalising behaviour problems in 3-year-old children: results from the Norwegian Mother and Child Cohort Study. Paediatr Perinat Epidemiol. 2016; 30(2): 190-200.
- 28Kallen B, Nilsson E, Otterblad OP. Delivery outcome after maternal use of drugs for migraine: a register study in Sweden. Drug Saf. 2011; 34(8): 691-703.
- 29Kallen B, Lygner PE. Delivery outcome in women who used drugs for migraine during pregnancy with special reference to sumatriptan. Headache. 2001; 41(4): 351-356.
- 30Olesen C, Steffensen FH, Sorensen HT, Nielsen GL, Olsen J. Pregnancy outcome following prescription for sumatriptan. Headache. 2000; 40(1): 20-24.
- 31Spielmann K, Kayser A, Beck E, Meister R, Schaefer C. Pregnancy outcome after anti-migraine triptan use: a prospective observational cohort study. Cephalalgia. 2018; 38(6): 1081-1092.
- 32 Drks. Fetotoxical Risk Analysis of Maternal Triptan Therapy During Pregnancy in the Context of Migraine Disorder; 2019. http://wwwwhoint/trialsearch/trial2aspx?Trialid=drks00007660. Accessed August 18, 2020.
- 33Castilla-Puentes R, Ford L, Manera L, Kwarta RF, Jr., Ascher S, Li Q. Topiramate monotherapy use in women with and without epilepsy: pregnancy and neonatal outcomes. Epilepsy Res. 2014; 108(4): 717-724.
- 34Govindappagari S, Grossman TB, Dayal AK, Grosberg BM, Vollbracht S, Robbins MS. Peripheral nerve blocks in the treatment of migraine in pregnancy. Obstet Gynecol. 2014; 124(6): 1169-1174.
- 35Scharff L, Marcus DA, Turk DC. Maintenance of effects in the nonmedical treatment of headaches during pregnancy. Headache. 1996; 36(5): 285-290.
- 36Hickling EJ, Silverman DJ, Loos W. A non-pharmacological treatment of vascular headache during pregnancy. Headache. 1990; 30(7): 407-410.
- 37Bhola R, Kinsella E, Giffin N, et al. Single-pulse transcranial magnetic stimulation (sTMS) for the acute treatment of migraine: evaluation of outcome data for the UK post market pilot program. J Headache Pain. 2015; 16:535.
- 38Bellos I, Pergialiotis V, Antsaklis A, Loutradis D, Daskalakis G. Safety of non-steroidal anti-inflammatory drugs in the postpartum period among women with hypertensive disorders of pregnancy: a meta-analysis. Ultrasound Obstet Gynecol. 2020; 56(3): 329–339.
- 39Hammers AL, Sanchez-Ramos L, Kaunitz AM. Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis. Am J Obstet Gynecol. 2015; 212(4): 505.e1-505.e13.
- 40Chaemsaithong P, Cuenca-Gomez D, Plana MN, Gil MM, Poon LC. Does low-dose aspirin initiated before 11 weeks’ gestation reduce the rate of preeclampsia? Am J Obstet Gynecol. 2020; 222(5): 437-450.
- 41Henderson JT, Whitlock EP, O'Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014; 160(10): 695-703.
- 42Coomarasamy A, Honest H, Papaioannou S, Gee H, Khan KS. Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. Obstet Gynecol. 2003; 101(6): 1319-1332.
- 43Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007; 2:Cd004659.
- 44Hamulyák EN, Scheres LJ, Marijnen MC, Goddijn M, Middeldorp S. Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss. Cochrane Database Syst Rev. 2020; 5(5):Cd012852.
- 45Maze D, Kazi S, Gupta V, et al. Association of treatments for myeloproliferative neoplasms during pregnancy with birth rates and maternal outcomes: a systematic review and meta-analysis. JAMA Netw Open. 2019; 2(10):e1912666.
- 46Veroniki AA, Cogo E, Rios P, et al. Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med. 2017; 15(1): 95.
- 47Veroniki AA, Rios P, Cogo E, et al. Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis. BMJ Open. 2017; 7(7):e017248.
- 48Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev. 2016; 11:Cd010224.
- 49Yakoob MY, Bateman BT, Ho E, et al. The risk of congenital malformations associated with exposure to beta-blockers early in pregnancy: a meta-analysis. Hypertension. 2013; 62(2): 375-381.
- 50Abalos E, Duley L, Steyn DW, Gialdini C. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev. 2018; 10:Cd002252.
- 51Tietjen GE, Herial NA, Utley C, White L, Yerga-Woolwine S, Joe B. Association of von Willebrand factor activity with ACE I/D and MTHFR C677T polymorphisms in migraine. Cephalalgia. 2009; 29(9): 960-968.
- 52Bellos I, Pergialiotis V, Papapanagiotou A, Loutradis D, Daskalakis G. Comparative efficacy and safety of oral antihypertensive agents in pregnant women with chronic hypertension: a network metaanalysis. Am J Obstet Gynecol. 2020; 223(4): 525–537.
- 53Kaplan YC, Richardson JL, Keskin-Arslan E, Erol-Coskun H, Kennedy D. Use of ondansetron during pregnancy and the risk of major congenital malformations: a systematic review and meta-analysis. Reprod Toxicol. 2019; 86: 1-13.
- 54Picot C, Berard A, Grenet G, Ripoche E, Cucherat M, Cottin J. Risk of malformation after ondansetron in pregnancy: an updated systematic review and meta-analysis. Birth Defects Res. 2020; 112(13): 996-1013.
- 55Coughlin CG, Blackwell KA, Bartley C, Hay M, Yonkers KA, Bloch MH. Obstetric and neonatal outcomes after antipsychotic medication exposure in pregnancy. Obstet Gynecol. 2015; 125(5): 1224-1235.
- 56Terrana N, Koren G, Pivovarov J, Etwel F, Nulman I. Pregnancy outcomes following in utero exposure to second-generation antipsychotics: a systematic review and meta-analysis. J Clin Psychopharmacol. 2015; 35(5): 559-565.
- 57Etwel F, Faught LH, Rieder MJ, Koren G. The risk of adverse pregnancy outcome after first trimester exposure to H1 antihistamines: a systematic review and meta-analysis. Drug Saf. 2017; 40(2): 121-132.
- 58Li CM, Zhernakova A, Engstrand L, Wijmenga C, Brusselaers N. Systematic review with meta-analysis: the risks of proton pump inhibitors during pregnancy. Aliment Pharmacol Ther. 2020; 51(4): 410-420.
- 59McDonagh M, Matthews A, Phillipi C, et al. Antidepressant treatment of depression during pregnancy and the postpartum period. Evid Rep Technol Assess (Full Rep). 2014; 216: 1-308.
- 60McDonagh MS, Matthews A, Phillipi C, et al. Depression drug treatment outcomes in pregnancy and the postpartum period: a systematic review and meta-analysis. Obstet Gynecol. 2014; 124(3): 526-534.
- 61Dolovich LR, Addis A, Vaillancourt JM, Power JD, Koren G, Einarson TR. Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies. BMJ. 1998; 317(7162): 839-843.
- 62Enato E, Moretti M, Koren G. The fetal safety of benzodiazepines: an updated meta-analysis. J Obstet Gynaecol Can. 2011; 33(1): 46-48.
- 63Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology. 2000; 62(6): 385-392.
- 64Makrides M, Crosby DD, Bain E, Crowther CA. Magnesium supplementation in pregnancy. Cochrane Database Syst Rev. 2014; 4:Cd000937.
- 65Marchenko A, Etwel F, Olutunfese O, Nickel C, Koren G, Nulman I. Pregnancy outcome following prenatal exposure to triptan medications: a meta-analysis. Headache. 2015; 55(4): 490-501.
- 66Masarwa R, Levine H, Gorelik E, Reif S, Perlman A, Matok I. Prenatal exposure to acetaminophen and risk for attention deficit hyperactivity disorder and autistic spectrum disorder: a systematic review, meta-analysis, and meta-regression analysis of cohort studies. Am J Epidemiol. 2018; 187(8): 1817-1827.
- 67Bain ES, Middleton PF, Crowther CA. Maternal adverse effects of different antenatal magnesium sulphate regimens for improving maternal and infant outcomes: a systematic review. BMC Pregnancy Childbirth. 2013; 13: 195.
- 68Mehvar R, Brocks DR. Stereospecific pharmacokinetics and pharmacodynamics of beta-adrenergic blockers in humans. J Pharm Pharm Sci. 2001; 4(2): 185-200.
- 69Zisaki A, Miskovic L, Hatzimanikatis V. Antihypertensive drugs metabolism: an update to pharmacokinetic profiles and computational approaches. Curr Pharm Des. 2015; 21(6): 806-822.
- 70Davis RL, Eastman D, McPhillips H, et al. Risks of congenital malformations and perinatal events among infants exposed to calcium channel and beta-blockers during pregnancy. Pharmacoepidemiol Drug Saf. 2011; 20(2): 138-145.
- 71Duan L, Ng A, Chen W, et al. β-Blocker exposure in pregnancy and risk of fetal cardiac anomalies. JAMA Intern Med. 2017; 177(6): 885-887.