Management of Hereditary Angioedema in Pediatric, Pregnant, and Breast-Feeding Patients: An Expert Opinion – A Secondary Publication
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Hereditary angioedema



Submitted : 2024-01-29
Accepted : 2024-02-13
Published : 2024-02-28


Hereditary angioedema (HAE) is a rare inherited condition marked by recurrent skin and submucosal edema. HAE is caused by a C1 inhibitor deficiency or decreased C1 inhibitor function. The initial attack may occur during childhood or pregnancy, with symptoms ranging from classic angioedema to nonspecific stomach cramps. In this review, we discuss strategies for children and pregnant women to manage HAE attacks effectively and safely in light of the recent increase in HAE diagnosis. To begin, an aggressive work-up is necessary to confirm HAE-1/2 and to determine the most effective countermeasures. Secondly, in the event of an acute attack, plasma-derived C1-inhibitor is the first line of defense for children and pregnant women. Icatibant is also appropriate for use, except in pregnant women. Fresh frozen plasma (FFP) may be suggested as an alternative. Thirdly, proactive measures to prevent HAE attacks should be considered whenever a procedure is performed that may result in an exacerbation. Finally, FFP, attenuated androgen, and antifibrinolytic agents are recommended for long-term prophylaxis in South Korea where the C1 inhibitor is scarce. However, when making a decision, it is necessary to consider both the efficacy and the risk of adverse effects. For proper management, written action plans and first-aid kits are required. The action plans should be customized to the patient’s unique circumstances.


Farkas H, Harmat G, Füst G, et al., 2002, Clinical Management of Hereditary Angio-Oedema in Children. Pediatr Allergy Immunol, 13(3): 153–161.

Boyle RJ, Nikpour M, Tang MLK, 2005, Hereditary Angio-Oedema in Children: A Management Guideline. Pediatr Allergy Immunol, 16(4): 288–294.

Johnston DT, Smith RC, 2020, Hereditary Angioedema: Special Considerations in Children. Allergy Asthma Proc, 41(Suppl 1): S43–S46.

Caballero T, Canabal J, Rivero-Paparoni D, 2014, Management of Hereditary Angioedema in Pregnant Women: A Review. Int J Womens Health, 6: 839–848.

González-Quevedo T, Larco JI, Marcos C, et al., 2016, Management of Pregnancy and Delivery in Patients with Hereditary Angioedema Due to C1 Inhibitor Deficiency. J Investig Allergol Clin Immunol, 26(3): 161–167.

Shin M, Ahn K, 2013, A Case of Hereditary Angioedema in a 7-Year-Old Korean Girl. Allergy Asthma Immunol Res, 5(1): 59–61.

Jung JW, Park SY, Yoon SY, et al., 2022, Diagnosis and Treatment of Hereditary Angioedema: An Expert Opinion. Allergy Asthma Respir Dis, 10: 80–88.

Bork K, Meng G, Staubach P, et al., 2006, Hereditary Angioedema: New Findings Concerning Symptoms, Affected Organs, and Course. Am J Med, 119(3): 267–274.

Maurer M, Magerl M, 2021, Differences and Similarities in the Mechanisms and Clinical Expression of Bradykinin-Mediated vs. Mast Cell-Mediated Angioedema. Clin Rev Allergy Immunol, 61(1): 40–49.

Cicardi M, Zuraw BL, 2018, Angioedema Due to Bradykinin Dysregulation. J Allergy Clin Immunol Pract, 6(4): 1132–1141.

Maurer M, Margerl M, Betschel S, et al., 2022, The International WAO/EAACI Guideline for the Management of Hereditary Angioedema – The 2021 Revision and Update. Allergy, 77(7): 1961–1990.

Magerl M, Germenis AE, Maas C, et al., 2017, Hereditary Angioedema with Normal C1 Inhibitor: Update on Evaluation and Treatment. Immunol Allergy Clin North Am, 37(3): 571–584.

Bork K, Siedlecki K, Bosch S, et al., 2000, Asphyxiation by Laryngeal Edema in Patients with Hereditary Angioedema. Mayo Clin Proc, 75(4): 349–354.

Christiansen SC, Davis DK, Castaldo AJ, et al., 2016, Pediatric Hereditary Angioedema: Onset, Diagnostic Delay, and Disease Severity. Clin Pediatr (Phila), 55(10): 935–942.

Jung JW, Suh DI, Park HJ, et al., 2018, Clinical Features of Hereditary Angioedema in Korean Patients: A Nationwide Multicenter Study. Int Arch Allergy Immunol, 176(3–4): 272–279.

Bork K, Hardt J, Schicketanz KH, et al., 2003, Clinical Studies of Sudden Upper Airway Obstruction in Patients with Hereditary Angioedema Due to C1 Esterase Inhibitor Deficiency. Arch Intern Med, 163(10): 1229–1235.

Martinez-Saguer I, Graff J, Rusicke E, et al., 2013, Does Early Clinical Manifestation of Hereditary Angioedema (HAE) Influence the Clinical Course of the Disease? J Allergy Clin Immunol, 131: AB30.

Martinez-Saguer I, Farkas H, 2016, Erythema Marginatum as an Early Symptom of Hereditary Angioedema: Case Report of 2 Newborns. Pediatrics, 137(2): e20152411.

Wahn V, Aberer W, Aygören-Pu?rsu?n E, et al., 2020, Hereditary Angioedema in Children and Adolescents – A Consensus Update on Therapeutic Strategies for German-Speaking Countries. Pediatr Allergy Immunol, 31(8): 974–989.

Farkas H, Martinez-Saguer I, Bork K, et al., 2017, International Consensus on the Diagnosis and Management of Pediatric Patients with Hereditary Angioedema with C1 Inhibitor Deficiency. Allergy, 72(2): 300–313.

Grumach AS, Ceccon ME, Rutz R, et al., 2014, Complement Profile in Neonates of Different Gestational Ages. Scand J Immunol, 79(4): 276–281.

Aabom A, Andersen KE, Fagerberg C, et al., 2017, Clinical Characteristics and Real-Life Diagnostic Approaches in All Danish Children with Hereditary Angioedema. Orphanet J Rare Dis, 12(1): 55.

Pedrosa M, Phillips-Angles E, Lopez-Lera A, et al., 2016, Complement Study Versus CINH Gene Testing for the Diagnosis of Type I Hereditary Angioedema in Children. J Clin Immunol, 36(1): 16–18.

Pappalardo E, Caccia S, Suffritti C, et al., 2008, Mutation Screening of C1 Inhibitor Gene in 108 Unrelated Families with Hereditary Angioedema: Functional and Structural Correlates. Mol Immunol, 45(13): 3536–3544.

Caballero T, Farkas H, Bouillet L, et al., 2012, 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, 129(2): 308–320.

Germenis AE, Margaglione M, Pesquero JB, et al., 2020, International Consensus on the Use of Genetics in the Management of Hereditary Angioedema. J Allergy Clin Immunol Pract, 8(3): 901–911.

Salguero CAS, Chacon AIS, 2016, HAE in Children- What is the Best Treatment Strategy? Int J Aller Medications, 2(1): 016.

Bork K, Hardt J, Staubach-Renz P, et al., 2011, Risk of Laryngeal Edema and Facial Swellings After Tooth Extraction in Patients with Hereditary Angioedema With and Without Prophylaxis with C1 Inhibitor Concentrate: A Retrospective Study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 112(1): 58–64.

Farkas H, Zotter Z, Csuka D, et al., 2012, Short-Term Prophylaxis in Hereditary Angioedema Due to Deficiency of the C1-Inhibitor – A Long-Term Survey. Allergy, 67(12): 1586–1593.

Caballero T, Maurer M, Longhurst HJ, et al., 2016, Triggers and Prodromal Symptoms of Angioedema Attacks in Patients with Hereditary Angioedema. J Investig Allergol Clin Immunol, 26(6): 383–386.

Busse PJ, Christiansen SC, Riedl MA, et al., 2021, US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema. J Allergy Clin Immunol Pract, 9(1): 132–150.e3.

Zotter Z, Csuka D, Szabo E, et al., 2014, The Influence of Trigger Factors on Hereditary Angioedema Due to C1-Inhibitor Deficiency. Orphanet J Rare Dis, 9: 44.

Farkas H, Varga L, Szeplaki G, et al., 2007, Management of Hereditary Angioedema in Pediatric Patients. Pediatrics, 120(3): e713–e722.

Australasian Society of Clinical Immunology and Allergy, 2022, ASCIA HAE Position Paper and Management Plan, viewed 26 Mar 2022,

Fijen LM, Levi M, Cohn DM, 2021, COVID-19 Vaccination and the Risk of Swellings in Patients with Hereditary Angioedema. J Allergy Clin Immunol Pract, 9(11): 4156–4158.

Czaller I, Visy B, Csuka D, et al., 2010, 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, 152(1): 44–49.

Martinez-Saguer I, Rusicke E, Aygören-Pu?rsu?n E, et al., 2010, Characterization of Acute Hereditary Angioedema Attacks During Pregnancy and Breast-Feeding and Their Treatment with C1 Inhibitor Concentrate. Am J Obstet Gynecol, 203(2): 131.e1–7.

Satomura A, Fujita T, Nakayama T, 2018, Comparison of the Frequency of Angioedema Attack, Before and During Pregnancy, in a Patient with Type I Hereditary Angioedema. Intern Med, 57(5): 751–755.

de Rojas DHF, Ibañez E, Longhurst H, et al., 2015, Treatment of HAE Attacks in the Icatibant Outcome Survey: An Analysis of Icatibant Self-Administration versus Administration by Health Care Professionals. Int Arch Allergy Immunol, 167(1): 21–28.

Ogston D, Walker J, Campbell DM, 1981, C1 Inactivator Level in Pregnancy. Thromb Res, 23(4–5): 453–455.

Kaminsky LW, Kelbel T, Ansary F, et al., 2017, Multiple Doses of Icatibant Used During Pregnancy. Allergy Rhinol (Providence), 8(3): e178–e181.

Farkas H, K?halmi KV, Veszeli N, et al., 2016, First Report of Icatibant Treatment in a Pregnant Patient with Hereditary Angioedema. J Obstet Gynaecol Res, 42(8): 1026–1028.

Zanichelli A, Mansi M, Periti G, 2015, Icatibant Exposure During Pregnancy in a Patient with Hereditary Angioedema. J Investig Allergol Clin Immunol, 25(6): 447–449.

Galan HL, Reedy MB, Starr J, et al., 1996, Fresh Frozen Plasma Prophylaxis for Hereditary Angioedema During Pregnancy. A Case Report. J Reprod Med, 41(7): 541–544.

Nathani F, Sullivan H, Churchill D, 2006, Pregnancy and C1 Esterase Inhibitor Deficiency: A Successful Outcome. Arch Gynecol Obstet, 274(6): 381–384.

Caliskaner Z, Ozturk S, Gulec M, et al., 2007, A Successful Pregnancy and Uncomplicated Labor with C1INH Concentrate Prophylaxis in a Patient with Hereditary Angioedema. Allergol Immunopathol (Madr), 35(3): 117–119.

Farkas H, Csuka D, Tóth F, et al., 2012, Successful Pregnancy Outcome After Treatment with C1-Inhibitor Concentrate in a Patient with Hereditary Angioedema and a History of Four Miscarriages. Eur J Obstet Gynecol Reprod Biol, 165(2): 366–367.

Brunskill PJ, 1992, The Effects of Fetal Exposure to Danazol. Br J Obstet Gynaecol, 99(3): 212–215.

Wentz AC, 1982, Adverse Effects of Danazol in Pregnancy. Ann Intern Med, 96(5): 672–673.

Gilad O, Merlob P, Stahl B, et al., 2014, Outcome Following Tranexamic Acid Exposure During Breastfeeding. Breastfeed Med, 9(8): 407–410.

Saule C, Boccon-Gibod I, Fain O, et al., 2013, Benefits of Progestin Contraception in Non-Allergic Angioedema. Clin Exp Allergy, 43(4): 475–482.