Urticaria and Angioedema

  • Shyam R. Joshi
  • David A. KhanEmail author


Urticaria and angioedema can manifest throughout pregnancy with an impact ranging from a decline in one’s quality of life to a potentially life-threatening situation in some cases of hereditary angioedema. Management should be tailored for each patient based on her history, personal priorities, severity of disease, and potential complications. As medication use is typically avoided in pregnancy if possible, due to actual or perceived risks to the fetus, women are often undertreated. In women with pre-existing chronic urticaria/angioedema, a thorough conversation between the clinician and patient should take place, ideally prior to conception, on the risks and benefits of therapy throughout pregnancy and lactation. Both acute and chronic urticaria present similarly in pregnant and nonpregnant patients. They should both be managed with second-generation H1 antihistamines as first-line therapy as they have reassuring human safety data during pregnancy. First-generation H1 antihistamines are generally considered second-line agents due to their sedating effects. Systemic steroids may have a role in short-term management but should never be used as chronic treatment for urticarial lesions. The use of omalizumab for chronic urticaria during pregnancy appears to be a safe and effective option, but data remain limited, and therefore omalizumab should be used only after a failure of first-line treatment. Special considerations exist for lactating mothers with urticaria. Second-generation H1 antihistamines again are the preferred therapy due to very low levels being detected in breast milk. Hereditary angioedema (HAE) is due to dysfunction of C1 inhibitor and can have an unpredictable course during pregnancy with a slight majority of women reporting an aggravation of symptoms. The safest option for acute exacerbations, short-term prophylaxis, and chronic prophylaxis is C1-INH concentrate. Other therapies for HAE including attenuated androgens, fresh frozen plasma, tranexamic acid, icatibant, and ecallantide have not been shown to be safe to use during pregnancy or have had inferior outcomes.


Urticaria Angioedema Pregnancy Chronic idiopathic urticaria Progesterone Antihistamines Omalizumab C1 esterase inhibitor 


  1. 1.
    McKee WD. The incidence and familial occurrence of allergy. J Allergy Ther. 1966;38(4):226–35.Google Scholar
  2. 2.
    Sheldon JM, Mathews KP, Lovell RG. The vexing urticaria problem: present concepts of etiology and management. J Allergy Ther. 1954;25(6):525–60.Google Scholar
  3. 3.
    Simonart T, Askenasi R, Lheureux P. Particularities of urticaria seen in the emergency department. Eur J Emerg Med. 1994;1(2):80–2.PubMedGoogle Scholar
  4. 4.
    Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133(5):1270–7.PubMedGoogle Scholar
  5. 5.
    Frigas E, Nzeako UC. Angioedema. Pathogenesis, differential diagnosis, and treatment. Clin Rev Allergy Immunol. 2002;23(2):217–31.PubMedGoogle Scholar
  6. 6.
    Malbrán E, Fernández Romero D, Juri MC, Larrauri BJ, Malbrán A. Epidemiology of angioedema without wheals in an allergy and immunology center. Med (B Aires). 2015;75(5):273–6.Google Scholar
  7. 7.
    Gabbe SG, Niebyl JR, Simpson JL, Landon MB, Galan HL, Jauniaux ERM, et al. Obstetrics: normal and problem pregnancies. 7th ed. Philadelphia: Elsevier; 2016.Google Scholar
  8. 8.
    Zaitsu M, Narita S, Lambert KC, Grady JJ, Estes DM, Curran EM, et al. Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx. Mol Immunol. 2007;44(8):1977–85.PubMedGoogle Scholar
  9. 9.
    Cocchiari R, Albeggiani G, Di Trapani G, Azzolina A, Lampiasi N, Rizzo F, et al. Modulation of rat peritoneal mast cell and human basophil histamine release by estrogens. Int Arch Allergy Appl Immunol. 1990;93(2–3):192–7.Google Scholar
  10. 10.
    Mittman RJ, Bernstein DI, Steinberg DR, Enrione M, Bernstein IL. Progesterone-responsive urticaria and eosinophilia. J Allergy Clin Immunol. 1989;84(3):304–10.PubMedGoogle Scholar
  11. 11.
    Vasiadi M, Kempuraj D, Boucher W, Kalogeromitros D, Theoharides TC. Progesterone inhibits mast cell secretion. Int J Immunopathol Pharmacol. 2006;19(4):787–94.PubMedGoogle Scholar
  12. 12.
    Kasperska-Zajac A, Brzoza Z, Rogala B. Sex hormones and urticaria. J Dermatol Sci. 2008;52(2):79–86.PubMedGoogle Scholar
  13. 13.
    Incorvaia E, Sicouri L, Petersen-Mahrt SK, Schmitz KM. Hormones and AID: balancing immunity and autoimmunity. Autoimmunity. 2013;46(2):128–37.PubMedGoogle Scholar
  14. 14.
    Zierau O, Zenclussen AC, Jensen F. Role of female sex hormones. Estradiol and progesterone, in mast cell behavior. Front Immunol. 2012;3:169.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Slater JE, Kaliner M. Effects of sex hormones on basophil histamine release in recurrent idiopathic anaphylaxis. J Allergy Clin Immunol. 1987;80:285–90.PubMedGoogle Scholar
  16. 16.
    Kasperska-Zajac A, Brzoza Z, Rogala B. Serum concentration of dehydroepiandrosterone sulphate in female patients with chronic idiopathic urticaria. J Dermatol Sci. 2006;41(1):80–1.PubMedGoogle Scholar
  17. 17.
    Thon V, Harle P, Scholmerich J, Kuklinek P, Lokaj J, Straub RH. Lack of dehydroepiandrosterone in type I and II hereditary angioedema and role of danazol in steroid hormone conversion. Allergy. 2007;62(11):1320–5.PubMedGoogle Scholar
  18. 18.
    Tagawa N, Hidaka Y, Takano T, Shimaoka Y, Kobayashi Y, Amino N. Serum concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate and their relation to cytokine production during and after normal pregnancy. Clin Chim Acta. 2004;340(1–2):187–93.PubMedGoogle Scholar
  19. 19.
    Aoki T, Kojima M, Horiko T. Acute urticaria: history and natural course of 50 cases. J Dermatol. 1994;21(2):73–7.PubMedGoogle Scholar
  20. 20.
    Sehgal VN, Rege VL. An interrogative study of 158 urticaria patients. Ann Allergy. 1973;31(6):279–83.PubMedGoogle Scholar
  21. 21.
    Sabroe RA. Acute Urticaria. Immunol Allergy Clin N Am. 2014;34(1):11–21.Google Scholar
  22. 22.
    Zuberbier T, Balke M, Worm M, Edenharter G, Maurer M. Epidemiology of urticaria: a representative cross-sectional population survey. Clin Exp Dermatol. 2010;35(8):869–73.PubMedGoogle Scholar
  23. 23.
    Kaplan A. Inflammation in chronic urticaria is not limited to the consequences of mast cell (or basophil) degranulation. Clin Exp Allergy. 2010;40(6):834–5.PubMedGoogle Scholar
  24. 24.
    Saini SS. Basophil responsiveness in chronic urticaria. Curr Allergy Asthma Rep. 2009;9(4):286–90.PubMedGoogle Scholar
  25. 25.
    Confino-Cohen R, Chodick G, Shalev V, Leshno M, Kimhi O, Goldberg A. Chronic urticaria and autoimmunity: associations found in a large population study. J Allergy Clin Immunol. 2012;129(5):1307–13.PubMedGoogle Scholar
  26. 26.
    Gruber BL, Baeza ML, Marcheses MJ, Agnello V, Kaplan AP. Prevalence and functional role of anti-IgE autoantibodies in urticarial syndromes. J Invest Dermatol. 1988;90(2):213–7.PubMedGoogle Scholar
  27. 27.
    Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW. Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med. 1993;328(22):1599–604.PubMedGoogle Scholar
  28. 28.
    Doong JC, Chichester K, Oliver ET, Schwartz LB, Saini SS. Chronic idiopathic urticaria: systemic complaints and their relationship with disease and immune measures. J Allergy Clin Immunol Pract. 2017;5(5):1314–8.PubMedGoogle Scholar
  29. 29.
    Amsler E, Augey F, Soria A, Baccon-Gibod I, Doutre MS, Mathelier-Fusade P, et al. Chronic urticaria and hormones: is there a link? J Eur Acad Dermatol Venereol. 2016;30(9):1527–30.PubMedGoogle Scholar
  30. 30.
    Snyder JL, Krishnaswamy G. Autoimmune progesterone dermatitis and its manifestation as anaphylaxis: a case report and literature review. Ann Allergy Asthma Immunol. 2003;90(5):469–77.PubMedGoogle Scholar
  31. 31.
    Li RC, Buchheit KM, Bernstein JA. Progestogen hypersensitivity. Curr Allergy Asthma Rep. 2018;18(1):1.PubMedGoogle Scholar
  32. 32.
    Bierman SM. Autoimmune progesterone dermatitis of pregnancy. Arch Dermatol. 1973;107(6):896–901.PubMedGoogle Scholar
  33. 33.
    Meggs WJ, Pescovitz OH, Metcalfe D, Loriaux DL, Cutler G, Kaliner M. Progesterone sensitivity as a cause of recurrent anaphylaxis. N Engl J Med. 1984;311(19):1236–8.PubMedGoogle Scholar
  34. 34.
    Foer D, Buchheit KM, Gargiulo AR, Lynch DM, Castells M, Wickner PG. Progestogen hypersensitivity in 24 cases: diagnosis, management, and proposed renaming and classification. J Allergy Clin Immunol Pract. 2016;4(4):723–9.PubMedGoogle Scholar
  35. 35.
    Taylor D, Pappo E, Aronson IK. Polymorphic eruption of pregnancy. Clin Dermatol. 2016;34(3):383–91.PubMedGoogle Scholar
  36. 36.
    Holmes RC, Black MM. The specific dermatoses of pregnancy. J Am Acad Dermatol. 1983;8(3):405–12.PubMedGoogle Scholar
  37. 37.
    Im S, Lee ES, Kim W, Song J, Kim J, Lee M, et al. Expression of progesterone receptor in human keratinocytes. J Korean Med Sci. 2000;15(6):647–54.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Ohel I, Levy A, Silberstein T, Holcberg G, Sheiner E. Pregnancy outcome of patients with pruritic urticarial papules and plaques of pregnancy. J Matern Fetal Neonatal Med. 2006;19(5):305–8.PubMedGoogle Scholar
  39. 39.
    Regnier S, Fermand V, Levy P, Uzan S, Aractingi S. A case-control study of polymorphic eruption of pregnancy. J Am Acad Dermatol. 2008;58(1):63–7.PubMedGoogle Scholar
  40. 40.
    Yancey KB. Herpes gestationis. Dermatol Clin. 1990;8(4):727–35.PubMedGoogle Scholar
  41. 41.
    Lehrhoff S, Pomeranz MK. Specific dermatoses of pregnancy and their treatment. Dermatol Ther. 2013;26(4):274–84.PubMedGoogle Scholar
  42. 42.
    Chi CC, Wang SH, Charles-Holmes R, Ambros-Rudolph C, Powell J, Jenkins R, et al. Pemphigoid gestationis: early onset and blister formation are associated with adverse pregnancy outcomes. Br J Dermatol. 2009;160(6):1222–8.PubMedGoogle Scholar
  43. 43.
    Amato L, Mei S, Gallerani I, Moretti S, Fabbri P. J Am Acad Dermatol. 2003;49(2):302–7.PubMedGoogle Scholar
  44. 44.
    Diav-Citrin O, Schechtman S, Aharonovich A, Moerman L, Arnon J, Wajnberg R, et al. Pregnancy outcome after gestational exposure to loratadine or antihistamines: a prospective controlled cohort study. J Allergy Clin Immunol. 2003;111(6):1239–43.PubMedGoogle Scholar
  45. 45.
    Etwel 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):121–32.PubMedGoogle Scholar
  46. 46.
    Gilboa SM, Ailes EC, Rai RP, Anderson JA, Honein MA. Expert Opin Drug Saf. 2014;13(12):167–98.Google Scholar
  47. 47.
    Moretti ME, Caprara D, Coutinho CJ, Bar-Oz B, Berkovitch M, Addis A, et al. Fetal safety of loratadine use in the first trimester of pregnancy: a multicenter study. J Allergy Clin Immunol. 2003;111(3):479–83.PubMedGoogle Scholar
  48. 48.
    Fedorowicz Z, van Zuuren EJ, Hu N. Histamine H2-receptor antagonists for urticaria. Cochrane Database Syst Rev. 2012;3:CD008596.Google Scholar
  49. 49.
    Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of Urticaria. The 2017 revision and update. Allergy. 2018.
  50. 50.
    Jain V, Gordon C. Managing pregnancy in inflammatory rheumatological diseases. Arthiritis Res Ther. 2011;13(1):206.Google Scholar
  51. 51.
    Bay Bjorn AM, Ehrenstein V, Hundborg HH, Nohr EA, Sorensen HT, Norgaard M. Use of corticosteroids in early pregnancy is not associated with risk of oral clefts and other congenital malformations in offspring. Am J Ther. 2014;21(2):73–80.PubMedGoogle Scholar
  52. 52.
    Sarkar M, Koren G, Kalra S, Ying A, Smorlesi C, De Santis M, et al. Montelukast use during pregnancy: a multicenter, prospective, comparative study of infant outcomes. Eur J Clin Pharmacol. 2009;65(12):1259–64.PubMedGoogle Scholar
  53. 53.
    Joshi S, Khan DA. The expanding field of biologics in the management of chronic urticaria. J Allergy Clin Immunol Pract. 2017;5(6):1489–99.PubMedGoogle Scholar
  54. 54.
    Namazy J, Cabana MD, Scheuerle AE, Thorp JM, Chen H, Carrigan G, et al. The Xolair Pregnancy Registry (EXPECT): the safety of omalizumab use during pregnancy. J Allergy Clin Immunol. 2015;135(2):407–12.PubMedGoogle Scholar
  55. 55.
    Rahimi R, Nikfar S, Rezaie A, Abdollahi M. Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicyclic acid drugs: a meta-analysis. Reprod Toxicol. 2008;25(2):271–5.PubMedGoogle Scholar
  56. 56.
    O’Brien TE. Excretion of drugs in human milk. Am J Hosp Pharm. 1974;31(9):844–54.PubMedGoogle Scholar
  57. 57.
    Hilbert J, Radwanski E, Affrime MB, Perentesis G, Symchowicz S, Zampaglione N. Excretion of loratadine in human breast milk. J Clin Pharmacol. 1988;28(3):234–9.PubMedGoogle Scholar
  58. 58.
    Ito S, Blajchman A, Stephenson M, Eliopoulos C, Koren G. Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. Am J Obstet Gynecol. 1993;168(5):1393–9.PubMedGoogle Scholar
  59. 59.
    Messinis IE, Souvatzoglou A, Fais N, Lolis D. Histamine H1 receptor participation in the control of prolactin secretion in postpartum. J Endocrinol Investig. 1985;8(2):143–6.Google Scholar
  60. 60.
    Lumry WR. Overview of epidemiology, pathophysiology, and disease progression in hereditary angioedema. Am J Manag Care. 2013;19(7 Suppl):s103–10.PubMedGoogle Scholar
  61. 61.
    Caballero T, Farkas H, Bouillet L, Bowen T, Gompel A, Fagerberg C, et al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol. 2012;129(2):308–20.PubMedGoogle Scholar
  62. 62.
    Cunningham DS, Jensen JT. Hereditary angioneurotic edema in the puerperium. A case report. J Reprod Med. 1991;36(4):312–3.PubMedGoogle Scholar
  63. 63.
    Cohen AJ, Laskin C, Tarlo S. C1 esterase inhibitor in pregnancy. J Allergy Clin Immunol. 1992;90(3 Pt 1):412–3.PubMedGoogle Scholar
  64. 64.
    Weiler CR, van Dellen RG. Genetic test indications and interpretations in patients with hereditary angioedema. Mayo Clin Proc. 2006;81(7):958–72.PubMedGoogle Scholar
  65. 65.
    Bouillet L, Longhurst H, Boccon-Gibod I, Bork K, Bucher C, Bygum A, et al. Disease expression in women with hereditary angioedema. Am J Obstet Gynecol. 2008;199(5):484.e1–4.Google Scholar
  66. 66.
    Czaller I, Visy B, Czuka D, Fust G, Toth F, Farkas H. The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey. Eur J Obstet Gynecol Reprod Biol. 2010;152(1):44–9.PubMedGoogle Scholar
  67. 67.
    Martinez-Saguer I, Rusicke E, Aygoren-Pursun E, Heller C, Klingebiel T, Kruez W. Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitory concentrate. Am J Obstet Gynecol. 2010;203(2):131.e1–7.Google Scholar
  68. 68.
    Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore). 1992;71(4):206–15.Google Scholar
  69. 69.
    Cicardi M, Aberer W, Banerji A, Bas M, Bernstein JA, Bork K, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy. 2014;69(5):602–16.PubMedGoogle Scholar
  70. 70.
    Caballero T, Canabal J, Rivero-Paparoni D, Cabanas R. Management of hereditary angioedema in pregnant women: a review. Int J Womens Health. 2014;6:839–48.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Kaminsky LW, Kelbel T, Ansary F, Craig T. Multiple doses of icatibant used during pregnancy. Allergy Rhinol (Providence). 2017;8(3):178–81.Google Scholar
  72. 72.
    Farkas H, Kohalmi KV, Veszeli N, Toth F, Varga L. First report of icatibant treatment in a pregnant patient with hereditary angioedema. J Obstet Gynaecol Res. 2016;42(8):1026–8.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Chan W, Berlin N, Sussman GL. Management of hereditary angioedema with C1-inhibitor concentrate during two successive pregnancies. Int J Gynaecol Obstet. 2013;120(2):189–90.PubMedGoogle Scholar
  74. 74.
    Cicardi M, Bergamaschini L, Cugno M, Hack E, Agostoni G, Agostoni A. Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience. J Allergy Clin Immunol. 1991;87(4):768–73.PubMedGoogle Scholar
  75. 75.
    Straka BT, Ramirez CE, Byrd JB, Stone E, Woodard-Grice A, Nian H, et al. Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema. J Allergy Clin Immunol. 2017;140(1):242–8.e2.PubMedGoogle Scholar
  76. 76.
    Sinert R, Levy P, Bernstein JA, Body R, Sivilotti MLA, Moellman J, et al. Randomized trial of icatibant for angiotensin-converting enzyme inhibitor-induced upper airway angioedema. J Allergy Clin Immunol Pract. 2017;5(5):1402–9.e3.PubMedGoogle Scholar
  77. 77.
    Sands MF, Blume JW, Schwartz SA. Successful treatment of 3 patients with recurrent idiopathic angioedema with omalizumab. J Allergy Clin Immunol. 2007;120(4):979–81.PubMedGoogle Scholar
  78. 78.
    Staubach P, Metz M, Chapman-Rothe N, Sider C, Brautigam M, Canvin K, et al. Effect of omalizumab on angioedema in H1-antihistamine-resistant chronic spontaneous urticaria patients: results from X-ACT, a randomized controlled trial. Allergy. 2016;71(8):1135–44.PubMedGoogle Scholar
  79. 79.
    Staubach P, Metz M, Chapman-Rothe N, Sieder C, Brautigam M, Maurer M, et al. Omalizumab rapidly improves angioedema-related quality of life in adult patients with chronic spontaneous urticaria: X-ACT study data. Allergy. 2017.

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Oregon Health and Science UniversityPortlandUSA
  2. 2.University of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations