Treatment of Hereditary Angioedema Attacks with Icatibant and Recombinant C1 Inhibitor During Pregnancy

Abstract

Purpose

Hereditary angioedema (HAE) is a rare disease caused by a C1 inhibitor (C1-INH) deficit. Clinically, HAE is manifested by repeated episodes of localized subcutaneous or submucosal oedema attacks. Managing HAE patients in pregnancy is challenging, since there are only limited data on the safety and efficacy of various therapeutic approaches.

Methods

We present our clinical experience treating acute HAE attacks during pregnancy in six consecutive patients.

Results

During the pregnancies, 79 HAE attacks occurred. The most frequent were abdominal 53 (67.1%) followed by peripheral 21 (26.6%), facial 10 (12.7%), and laryngeal 10 (12.7%) oedemas; 13 (16.5%) attacks were combined. Fifty (63.3%) attacks were treated with recombinant human C1-INH (rhC1-INH); 17 (21.5%) with plasma-derived, pasteurized, nanofiltered C1-INH (pnfC1-INH); 13 (16.5%) with icatibant; and 1 (1.3%) with plasma-derived, nanofiltered C1-INH (nfC1-INH). Treatment had to be repeated in 5 attacks (6.3%). All six deliveries (one caesarean section and five spontaneous vaginal deliveries) were complication free. All pregnancies went to the full term and the patients delivered healthy babies with a birth weight ranging from 2850 to 3690 g. No congenital abnormalities were detected in the neonates. No abortions occurred.

Conclusions

Our results show good C1-INH or icatibant treatment efficacy for HAE attacks in pregnancy. The treatment by the first drug used was effective in 93.7% of all attacks. In 6.3% of attacks, a second treatment had to be used. No adverse effects were observed.

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References

  1. 1.

    Zuraw BL. Hereditary angioedema. N Engl J Med. 2008;359(10):1027–36.

    CAS  Article  Google Scholar 

  2. 2.

    Cicardi M, Bork K, Caballero T, Craig T, Li HH, Longhurst H, et al. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy. 2012;67(2):147–57.

    CAS  Article  Google Scholar 

  3. 3.

    Bouillet L. Hereditary angioedema in women. Allergy Asthma Clin Immunol. 2010 Jul 28;6(1):17.

    Article  Google Scholar 

  4. 4.

    Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267–74.

    Article  Google Scholar 

  5. 5.

    Farkas H, Csuka D, Toth F, Koszegi L, Varga L. 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. 2012;165(2):366–7.

    Article  Google Scholar 

  6. 6.

    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.

    Article  Google Scholar 

  7. 7.

    Farkas H, Kőhalmi KV, Veszeli N, Tóth F, Varga L. First report of icatibant treatment in a pregnant patient with hereditary angioedema. J Obstet Gynaecol Res. 2016 Aug;42(8):1026–8.

    Article  Google Scholar 

  8. 8.

    Zanichelli A, Mansi M, Periti G. Icatibant exposure during pregnancy in a patient with hereditary angioedema. J Investig Allergol Clin Immunol. 2015;25(6):447–9.

    CAS  PubMed  Google Scholar 

  9. 9.

    Hakl R, Kuklinek P, Litzman J. Treatment of acute hereditary angioedema attacks with recombinant C1inhibitor during pregnancy – a single case experience. Allergy. 2014;69(Suppl. 99):497.

    Google Scholar 

  10. 10.

    Visy B, Füst G, Varga L, Szendei G, Takács E, Karádi I, et al. Sex hormones in hereditary angioneurotic oedema. Clin Endocrinol. 2004;60(4):508–15.

    CAS  Article  Google Scholar 

  11. 11.

    Steiner UC, Weber-Chrysochoou C, Helbling A, Scherer K, Grendelmeier PS, Wuillemin WA. Hereditary angioedema due to C1 - inhibitor deficiency in Switzerland: clinical characteristics and therapeutic modalities within a cohort study. Orphanet J Rare Dis. 2016 Apr 21;11:43.

    Article  Google Scholar 

  12. 12.

    Moldovan D, Bernstein JA, Cicardi M. Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency. Immunotherapy. 2015;7(7):739–52.

    CAS  Article  Google Scholar 

  13. 13.

    Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010;363(6):532–41.

    CAS  Article  Google Scholar 

  14. 14.

    González-Quevedo T, Larco JI, Marcos C, Guilarte M, Baeza ML, Cimbollek S, et al. Management of pregnancy and delivery in patients with hereditary angioedema due to C1 inhibitor deficiency. J Investig Allergol Clin Immunol. 2016;26(3):161–7.

    Article  Google Scholar 

  15. 15.

    Czaller I, Visy B, Csuka D, Füst G, Tóth 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.

    CAS  Article  Google Scholar 

  16. 16.

    Chinniah N, Katelaris CH. Hereditary angioedema and pregnancy. Aust N Z J Obstet Gynaecol. 2009;49(1):2–5.

    Article  Google Scholar 

  17. 17.

    Geng B, Riedl MA. HAE update: special considerations in the female patient with hereditary angioedema. Allergy Asthma Proc. 2013;34(1):13–8.

    CAS  Article  Google Scholar 

  18. 18.

    Martinez-Saguer I, Rusicke E, Aygoren-Pursun E, Heller C, Klingebiel T, Kreuz W. Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate. Am J Obstet Gynecol. 2010;203(2):131.e1–7.

    Article  Google Scholar 

  19. 19.

    Machado AM, Pires RM, Martins RO, Grumach AS. Pregnancy and postpartum in hereditary angioedema with C1 inhibitor deficit in women who have no access to therapy. J Investig Allergol Clin Immunol. 2017;27(5):322–3.

    Article  Google Scholar 

  20. 20.

    Skriver K, Radziejewska E, Silbermann JA, Donaldson VH, Bock SC. CpG mutations in the reactive site of human C1 inhibitor. J Biol Chem. 1989;264(6):3066–71.

    CAS  PubMed  Google Scholar 

  21. 21.

    Suffritti C, Zanichelli A, Maggioni L, Bonanni E, Cugno M, Cicardi M. High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency. Clin Exp Allergy. 2014;44(12):1503–14.

    CAS  Article  Google Scholar 

  22. 22.

    Rijavec M, Korošec P, Šilar M, Zidarn M, Miljković J, Košnik M. Hereditary angioedema nationwide study in Slovenia reveals four novel mutations in SERPING1 gene. PLoS One. 2013;8(2):e56712.

    CAS  Article  Google Scholar 

  23. 23.

    Sim DW, Park KH, Lee JH, Park JW. A case of type 2 hereditary angioedema with SERPING1 mutation. Allergy Asthma Immunol Res. 2017;9(1):96–8.

    Article  Google Scholar 

  24. 24.

    Committee for Medicinal Products for Human Use. Ruconest, conestat alfa: Annex I: Summary of Product characteristics. London: Committee for Medicinal Products for Human Use; 2017. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR _Product_Information/human/001223/WC500098542.pdf. Accessed 14 Aug 2018.

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Funding

This report was supported by MUNI/A/0925/2017 grant from the Ministry of Education, Youth and Sports of the Czech Republic and by grants 15-28732A, 16-34414A, and NV18-05-00330 from the Czech Ministry of Health.

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Correspondence to Roman Hakl.

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Conflict of Interest

Roman Hakl declares the following real or perceived conflicts of interest: Roman Hakl has received a travel grant from Pharming Group NV, CSL Behring and Shire.

Pavel Kuklínek has no conflict of interest.

Irena Krčmová has no conflict of interest.

Pavlína Králíčková has no conflict of interest.

Tomáš Freiberger has no conflict of interest.

Petr Janků has no conflict of interest.

Marcela Vlková has no conflict of interest.

Jiří Litzman has no conflict of interest.

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Hakl, R., Kuklínek, P., Krčmová, I. et al. Treatment of Hereditary Angioedema Attacks with Icatibant and Recombinant C1 Inhibitor During Pregnancy. J Clin Immunol 38, 810–815 (2018). https://doi.org/10.1007/s10875-018-0553-4

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Keywords

  • Hereditary angioedema
  • pregnancy
  • therapy
  • icatibant
  • recombinant C1 inhibitor